Journal of Cancer Research and Oncobiology

ISSN 2517-7370

Optimization Of Cancer Treatment Through Overcoming Drug Resistance

Yahya I. Elshimali1,2, Yong Wu1,2, Husseina Khaddour3,4, Yanyuan Wu1,2, Daniela Gradinaru4, Hema Sukhija1, Seyung S. Chung1,2, Jaydutt V. Vadgama1,2

1Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, USA

2David Geffen School of Medicine at UCLA, UCLA’s Jonsson Comprehensive Cancer Center, USA

3Faculty of Pharmacy, Mazzeh (17th April Street), Damascus University, Damascus, Syria

4Carol Davila - University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Biochemistry, Romania

Corresponding author

Yahya I. Elshimali
Department of Pathology and Oncology
UCLA School of Medicine & Charles R. Drew
University of Medicine and Science
Tel.: +1-818-515-7618
Fax: +1-818-994-9875.,

  • Received Date: January 01, 2018
  • Accepted Date: February 24, 2018
  • Published Date: February 27, 2018

DOI:   10.31021/jcro.20181107

Article Type:   Review Article

Manuscript ID:   JCRO-1-107

Publisher:   Boffin Access Limited.

Volume:   1.2

Journal Type:   Open Access

Copyright:   © 2018 Elshimali YI, et al.
Creative Commons Attribution 4.0


Elshimali YI , Wu Y, Khaddour H, Wu Y, Gradinaru D, et al. Optimization Of Cancer Treatment Through Overcoming Drug Resistance. J Cancer Res Oncobiol. 2018 Jan; 1(2):107


Cancer Drug resistance is a medical concern that requires extensive research and a thorough understanding in order to overcome. Remarkable achievements related to this field have been accomplished and further work is needed in order to optimize the cure for cancer and serve as the basis for precise medicine with few or no side effects.


Drug resistance; Malignancies; Molecular base; Optimal treatment


Drug Resistance has been reported for most current therapeutic agents against cancer cells, regardless of whether these are chemotherapeutic agents, target therapy or immunotherapy. Heterogeneity of tumor cells is considered an important factor for drug resistance. This heterogeneity is due to renewable small subpopulations of cells called stem-like cancer cells. It is highly possible that different generations of cells exist within one tumor, thus targeting them would result into alternative outcomes as some clones are sensitive and others are resistant to therapeutic agents. Further, tumor cells also have the capability to evolve over time; adding another challenge to treat cancer [1-3].

Initiation of chemo or target therapy for cancer patients depends on the clinical diagnosis, tumor stage, tumor type, molecular characteristics and gene expression.

In early stages, solid tumors (localized) can be cured by surgical excision, but in advanced stages, the chemotherapy, target therapy, immunotherapy, and/or the radiation therapy can be used before or after surgery in order to target the malignant cells that have spread beyond a surgeon’s reach [4]. Cytotoxic drugs are classified into four main categories; DNA Alkylating Agents, Antimetabolites, Intercalating Agents and Mitotic Inhibitors [5]. Chemotherapy drugs are not specific, while target therapies are more specific and have fewer side effects than standard chemotherapy. They were designed to block the receptors that are involved in tumor growth. Targeted therapies include hormone therapies, signal transduction inhibitors, apoptosis inducers, gene expression modulators, angiogenesis inhibitors, and toxin delivery molecules [6], whereas immunotherapies insvolve three general categories: checkpoint inhibitors, cytokines, Interferon and cancer vaccines [7]. The optimal application for cancer drugs can be determined by the genetic signature of every individual tumor case, thus identifying the best appropriate drug combination to be used and to avoid unnecessary toxicity. Although these treatments brought great success by prolonging the survival period, understanding the resistance to these agents will definitely optimize the cure for cancer and serve as the basis for precise medicine with less cytotoxicity [3].

Mechanisms of Resistance to Cancer Drugs

There are two types of drug resistance, one occurs prior to drug treatment known as primary or innate resistance, and the other develops over time post exposure to a given therapeutic agent known as acquired resistance; both being associated with genetic and epigenetic changes that occur within a cancer cell [8].

On the other hand, mechanisms of resistance to cancer drugs are divided into two broad categories: cellular mechanisms and non-cellular mechanisms. Cellular mechanisms address tumor cell-autonomous signaling pathways, insensitivity to natural growth arrest signals, abolishment of cell contact inhibition, the ability to evade apoptosis, and the role of the tumor microenvironment, whereas non-cellular mechanisms are related to pharmacological response [1]. Factors that are associated with tumor cell-intrinsic modifications include genetic alterations, chromatin modifications, enrichment of cancer stem/initiating cells, loss of cell polarity, alterations in cell-cell and cell-matrix adhesion, and deregulated receptor kinase signaling, which all together support detachment, migration and invasion of tumor cells which negatively influence the response to chemotherapy.

The interactions between tumor cells and non-transformed cells, such as stromal, endothelial, and immune response cells are other factors that manipulate tumorigenic events and responses to chemo, target, or immuno drugs [9-12]

Cellular mechanisms

Genetic mutations that promote cancer drug resistance: Mutations that result in over-expression of growth factors or downregulation of tumor suppressor genes will enhance cell proliferation and cancer drug resistance. Hence, pathways affected by these mutations include:

Activation of RAS/RAF/MEK/ERK signaling pathway: The RAS/RAF/MEK/ERK pathway is implicated in growth-factor mediated cell proliferation, differentiation, and cell death. Activation of this pathway will result in resistance to chemo drugs and target therapy.

Inducting signals of this pathway could be due to overexpression of EGFR or mutations of tyrosine kinases receptors (RTK) that turn them into an active state leading to the activation of downstream signaling cascade and promoting cancer cellular survival, proliferation, and up regulation of fatty acid synthase [13-16].

Mutation of KRAS may lead to constitutive activation of the signal transduction pathway, which is associated with development of resistance to anti-EGFR monoclonal antibody with agents like centuximab or panitumumab. B-Raf mutations have been frequently detected in melanoma and thyroid cancers, and resistance to chemotherapy was observed in ectopic activation of Raf doxorubicin treated tumors or paclitaxel treated breast cancer cells. Interestingly, inhibition of ERK pathway increases tumor cell resistance to ADM (Adriamycin) and GEM Gemcitabine [17-20]. More than 80% of patients with non-small-cell lung cancers (NSCLC) are over expressing EGFR1 in their tumor tissues indicating poor prognosis and resistance to chemotherapy, and only 10% of these patients respond to EGFR1-TKI (tyrosine kinase inhibitor) therapy. In order to overcome such resistance, a combination of target therapy against both EGFR and MEK is indicated and similar combination against EGFR and c-Met was also addressed in patients with lung fibrosis and who are expressing abundantly type I collagen in the tumor mass [21-24].

Other drugs that act on this pathway are Raf kinase inhibitors (sorafenib, encorafenib) and MEK inhibitors (cobimetinib, selumetinib and trametinib) [24].

Mutations observed in PTEN/PI3K/AKT/MTOR pathway: The PI3K/Akt/mTOR pathway is a central regulator in cancer cell proliferation, tumorigenesis, and metastasis. This pathway is comprised of three main driving molecules: PI3K (phosphoinositide 3-kinase), AKT, and MTOR (mammalian target of rapamycin) [25-28].

PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a dual protein and lipid phosphatase that is commonly mutated in many human malignancies. PETN was originally identified as a negative regulator of the PI3K leading to inactivation of AKT and MTOR signaling. Loss of PTEN results in reduced dephosphorylation of PIP3 (phosphoinositide 3,4,5-trisphosphate), which allows PI3K to phosphorylate PIP2 (phosphatidylinositol 4,5-bisphosphate) and enhances levels of PIP3. PIP3 induction activates AKt and causes increased cell size, cell proliferation, cell migration, cell survival, and resistance to chemotherapy. Loss of function of PTEN or constitutive activation in the gene encoding the catalytic subunit of PI3K (PIK3CA) results in resistance to Trastuzumab [27-31]. PTEN loss/mutation often co-exists with mutations in BRAF and KRAS, and preclinical studies suggested PTEN deficiency is associated with resistance to the EGFR inhibitors (cetuximab, gefitinib and erlotinib) for treatment of colorectal and lung cancer [28-32]. PTEN function and expression are modulated by germline and somatic PTEN mutations, genomic deletion, epigenetic silencing, post-transcriptional regulation, posttranslational regulation, and protein-protein interactions [27-33]. On the other hand, the alterations on both pathways RAS/RAF/MEK/ ERK and PTEN/PI3K/AKT/MTOR seem to have significant influence in melanoma progression, survival, and chemo-resistance [30-33].

AKT has been reported as a mediator in immune escape by activating the expression of immune checkpoint receptor programmed death-ligand 1 (PD-L1) in cancer cells avoiding their elimination by T lymphocytes [33].

Activation of NF-kB and STATs: Transcriptional factors of the NF-κB family and STAT3 are commonly regulating the expression of various genes associated with cell-cycle progression, angiogenesis, immune responses, apoptosis, metabolism, and cancer [34].

STAT3 can bind to and dissociate NF-kB:IkB complex, prolonging NF-kB retention in the nucleus, and promoting target gene activation [34-35]. The microenvironment of malignant cells, including immune cells and stromal cells, play an important role in the interaction between STAT3 and NF-κB through different kinds of cytokines. Thus, IKKβ inhibitors may slow down tumor growth and augment susceptibility to other therapeutic agents through preventing the expression of key tumor promoting cytokines. In addition, activated NF-κB has been identified as a key mechanism for the resistance to cisplatin. On the other hand, treatment of cells with AKT-NF-κB inhibitor abrogated the increased NF-κB activity in murine models results in sensitizing them to cisplatin induced apoptosis. However, disruption of either NF-κB or STAT3 signaling does not lead to cell death, therefore their inhibitors should be combined with cancerspecific cytotoxic drugs. In order to avoid the associated toxicity with theses inhibitors, it is desirable to consider more specific strategies that target NF-κB- and STAT3-dependent tumor promoting cytokines, such as TNF-α, IL-6 and IL-23. Also, a natural agent such as resveratrol can inhibit constitutive activation of both NF-kappa B and STAT3 resulting in down-regulation of cell proliferation [34-41].

Inactivation of Tumor Suppressor Genes (TSGs): Tumor suppressor genes maintain genomic stability, integrity of cell cycle, and prevent tumor development. Mutations of TSGs have been implicated in primary cancer development and in therapeutic resistance.

BRCA1 (Breast-Cancer Susceptibility Gene 1): BRCA1 functions as a tumor suppressor gene by regulating transcription, cell cycle checkpoint, and DNA repair. BRCA1 is frequently mutated in inherited breast and ovarian cancers though somatic mutations rarely reported in sporadic cases. Nevertheless, down-regulation of BRCA1 occurs more often with epigenetic modifications [42].

BRCA1 expression predicts the outcome of breast, lung, and ovarian cancer treatment with DNA-damage-based therapy and depending on the type of chemotherapeutics, BRCA1 can have either a positive or negative role in mediating chemo-sensitivity. When BRCA1 is inactivated by mutations, deletions, or down-regulation, cancer cells will no longer be able to repair the drug-induced DNA damage and will therefore trigger apoptosis, which explains why loss of BRCA1 sensitizes cancer cells to DNA damaging agents such as cisplatin and PARP [poly (ADP-ribose) polymerase] inhibitors. Similar findings have been applied to basal-like breast cancer which is characterized by being triple negative and aggressive [42-44]. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found in 11 to 42% of these tumors, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors exploit this deficiency through a synthetic lethality and are considered as promising anticancer therapies, especially in patients harboring BRCA1 or BRCA 2 mutations [44].

On the other hand, in response to microtubule damage induced by anti-microtubule agents such as paclitaxel or docetaxel, BRCA1 is activated to induce mitotic arrest and apoptosis by transcriptionally activating the spindle assembly checkpoint protein MAD2 (myoadenylate deaminase 2), which results in the activation of the JNK pathway via direct interaction with the JNK–MEKK3/ERK complex. Therefore, when BRCA1 is lost, the cancer cells will no longer activate the mitotic spindle checkpoint protein MAD2, and subsequent activation of the pro-apoptotic JNK pathway will cause resistance to the anti-microtubule agent [44-45].

In epithelial ovarian cancer, low let-7e (21-nucleotide regulatory microRNA) [46] leads to activation of BRCA1 and Rad 51 (339-amino acid protein that plays a major role in homologous recombination of DNA during double strand break repair) [47]. With the subsequent enhancement of double strand break repair causing cisplatinresistance, re-expression of let-7e might be an effective strategy for overcoming chemo-resistance [45].

(Retinoblastoma gene): Over-expression of Rb gene is considered an important marker for predicting chemotherapeutic response. Yet, several studies revealed conflicting evidence regarding the loss of Rb gene or not yielding chemo resistance [43].

TP53 Gene: TP53 is one of the most well-known tumor suppressor genes. Mutant p53 not only functions as a tumor suppressor, but can also exert tumor-promoting effects. Hence, the majority of human cancers show the inactivation of the p53 pathway.

Loss of p53 causes drug resistance due to down-regulation of pro-apoptotic genes such as PUMA (p53 up-regulated modulator of apoptosis), Bax, Bid,andNoxa.

On the other hand, PTEN can have tumor promoting effects on cells expressing mutant p53; therefore p53 status should be determined when PTEN is involved in a pathway of therapeutic interest [43-49].

The Hippo Tumor Suppressor Pathway: The Hippo pathway is an onco-suppressor signaling cascade that plays a major role in the control of cell growth, tissue homoeostasis, organ size, stem cell renewal, and the response of cancer cells to chemotherapy [50].

It is composed of three components: cell surface upstream regulators including cell adhesion molecules and cell polarity complexes; a kinase cascade comprising two serine-threonine kinases with regulators and adaptors; and a downstream target, a transcription coactivator [49,50]. In this pathway, the Mst1/2 (serine/threonine kinases/Hippo in Drosophila) and LATS1/2 (large tumor suppressor) together with the adaptor protein SAV1(Salvador homologue 1) and hMOB1 are the core players that transmit signals from upstream tumor suppressors molecules (Fat4, RASSF1A, Kibra, Merlin, hEx, and hWW45) to the downstream targets and tightly restrict the activities of homologous oncoproteins YAP (Yes kinase -associated protein) and (TAZ) (transcriptional co-activator with PDZ-binding motif) [50,51].

Hippo pathway negatively regulates the co-activator to restrict cell proliferation and to promote cell death. Hence, dysregulation of this pathway leads to aberrant activation of the transcription coactivator YAP and TAZ that contributes to tumorigenesis in several tissues. The localization of the MST1/2 and LATS1/2, whether it is cytoplasmic or nuclear, may impact the efficacy of the neoadjuvant therapy in breast cancer; being protective when expressed in the cytoplasm of tumor cells and in tumor-infiltrating lymphocytes. The dysfunction of this pathway is frequently detected in human cancers and correlates with a poor prognosis [52,53].

Molecules that affect cell cycle: Cell cycle progression is regulated by various complicated pathways that control every stage of the cell cycle (G0/G1, S and G2/M phases). Dysfunction or mutation of any regulator in each pathway may cause abnormal cell proliferation and may result in malignancy [54]. Invasion occurs primarily in a G1 /G0 cell cycle-arrested state, and expression of pro invasive genes driving epithelial to mesenchymal transition and F-actin cytoskeletal reorganization are associated with this cell cycle state [55-57]. Changes in the activity of cyclin-dependent kinase inhibitors CDK (cyclin-dependent kinase) (P21 and p27, INK4 family, P16, P21) and their target not only mediate the decision to enter or exit the cell cycle, but also may be critical to acquiring an invasive phenotype [58,59].

Targeting some molecules through these pathways could synergize or increase the effect of chemo drugs, but drug resistance can still occur as an evolving event through the course of treatment.

Of these molecules, these are important for cell cycle involved in chemo resistance CASC1 (CAncer Susceptibility Candidate 1), TRIM69 (Tripartite motif containing 69), FOXO1 (Forkhead box protein O1), Kin17 (DNA/RNA-binding protein KIN17), and (Short transient receptor potential channel 5) TrpC5 CASC1 is essential for microtubule polymerization of spindle assembly checkpoint and is frequently co-amplified with KRAS in lung tumors while TRIM 69 is important for formation of a bipolar spindle. Study shows that RNAimediated attenuation of CASC1 or TRIM69 inhibits tumor growth in vivo and thus it can be a target to overcome paclitaxel induced resistance.

FOXM1 facilitates DNA repair through regulating direct transcriptional target EXO1 (exonuclease 1) to prevent cancer cells from cisplatin-mediated apoptosis as observed in ovarian cancers [56-60].

Kin17 is a conserved nuclear protein that participates in DNA damage repair, DNA replication, and cell proliferation. Kin17 protein expression was up-regulated in patients exhibiting chemo resistance in oral squamous cell carcinoma.

Adriamycin-resistant human breast cancer cells possessed numerous TrpC5 containing extracellular vehicles (EVs) on the cell surface. Up-regulated TrpC5 accumulated in EVs is responsible for EV formation and EV trapping of chemotherapeutic drugs. Thus, using TrpC5-containing EVs could be used as a diagnostic biomarker for chemo resistant breast cancer [61].

Oxidative stress and tumor hypoxia

Oxidative stress: The interaction between tumor cells and incubated microenvironment, i.e. stromal cells, surrounded stroma, neo vasculatures, oxygen, and nutrient supplements are essential factors for tumor growth, invasion, and metastases.

Tumor cells gain fundamental adaptation to a new environment by utilizing energy and using glucose through aerobic and anaerobic pathways, revealing more capability to adapt to the new stressful or normal conditions than normal counterpart cells and eventually adding further means for drug resistance [62,63].

“Sorcin” is an important protein that is up-regulated under the stressful conditions of the endoplasmic reticulum (ER). It is a 22- kDa calcium-binding protein that regulates epithelial-mesenchymal transition and cancer stem cells (CSCs), partly through E-cadherin and vascular endothelial growth factor expression. Scorin enhances the accumulation of Ca (2+) in the endoplasmic reticulum (ER) in order to prevent ER stress and render cancer cells resistant to chemotherapeutic agents [64].

In contrast, RNAi-mediated silencing of sorcin activated caspase-3, caspase-12, and GRP78/BiP, triggers apoptosis through the mitochondrial pathway. Experiments on human colorectal cancer cells (CRC) showed over-expression of sorcin as an adaptive mechanism to prevent ER stress and escape apoptosis prompted by chemotherapeutic agents. Nevertheless, Scorin was found to induce low levels of paclitaxel resistance in human ovarian and breast cancer cells and is associated with multidrug resistance in leukemia cells as well [65].

On the other hand, over-expression of CARMA3 {CARD (Caspase recruitment domain) recruited membrane associated protein 3} in human epithelial ovarian cancer is also associated with cisplatin resistance [54].

The Nrf2 {NF-E2-related factor 2) antioxidant response pathway is the primary cellular defense against the cytotoxic effects of oxidative stress. Nrf2 increases the expression of several antioxidant enzymes and its overexpression in cancer is associated with negative roles against chemo agents such as cisplatin. Several drugs that stimulate the Nrf2 pathway are being studied for treatment of diseases that are caused by oxidative stress as well [66,67].

Kawata et. al. [68] analyzed the immunohistochemical results of anti-oxidant response genes on prostate cancer cells {NRF2 (nuclear factor erythroid 2–related factor 2) and NQO1(NAD(P)H Quinone Dehydrogenase 1)} and found that it was more up-regulated after hormone ablation in prostate carcinoma samples after ADT (androgen deprivation therapy) than in untreated specimens or in murine prostate glands after castration, suggesting that ADT induces cellular senescence processes accompanied by secretory phenotypes and anti-oxidant responses in prostate cancer cells. These cellular changes may be attractive targets for preventing endocrine resistance in prostate cancer as observed in treatment with the anti-oxidant agent NAC (N-acetyl-cysteine), which significantly suppressed SAβ-Gal (senescence-associated-ß-galactosidase) activity in androgensensitive human prostate cancer cells (LNCaP) [67,69].

Tumor hypoxia: The center of a solid tumor is highly hypoxic due to poor blood circulation and this hypoxia is considered to be a major contributor to drug resistance. Under severe hypoxia, gene expression of ubiquitously expressed key enzymes and transporters of folate metabolism, as well as nucleoside homeostasis are down regulated.

The activated hypoxia induced factors (HIFs) may induce the expression of numerous gene products that can be targets for therapy and ultimately decrease the drug resistance [69,70]. Examples of these targets are Pluripotency-associated transcription factors (Oct3/4, Nanog and Sox-2), CXCR4 (C-X-C chemokine receptor type 4), Snail, Twist, VEGF, and Micro RNAs [71].

On the other hand, Antifolates have a crucial role in the treatment of various cancers by inhibiting key enzymes in purine and thymidylate biosynthesis. Resistance to antifolates, which is associated with suppression of folate metabolism, may result from the failure of antifolates to induce DNA damage under hypoxia that is attributed to hypoxia-induced cell cycle arrest rather than a general anti-apoptotic mechanism [72,73].

The Role of (ABC) Transporter Proteins in Drug Resistance: A Family of energy-dependent multi-drug transporters known as ATPbinding cassette transporter proteins (ABC) plays remarkable roles in chemo drug resentence [74-76]. The role of transport proteins is decisive to maintain cellular homeostasis. They have normal chemo protective functions in cells throughout the body against metabolites, small molecules, drugs, and endogenous toxins.

In cancers, the cells utilize certain transporter proteins to efflux chemotherapeutic agents out of the cells in order to support their survival. However, several studies have suggested that these transporters may block the entry of chemotherapeutic agents as well. Nevertheless, chemotherapeutic drugs need to enter and remain inside the cells in order to be effective [77]. The ABC proteins transport various molecules across the cellular membranes, and of these proteins are P-glycoprotein 1 (permeability glycoprotein, Pgp) known as MDR1 (multidrug resistance protein 1) and MRP2 (multidrug resistance-associated protein 2). Hence, over-expression of P-glycoprotein (P-gp) encoded by MDR1 gene is one of the major causes of drug resistance [78,79].

Vascular cell adhesion molecule-1 or CD106 (VCAM-1) is a transmembrane glycoprotein similar to ABC transporter protein that activates TGFβ1 or IL-6 mediating cell migration and facilitates leukocyte adhesion, leukocyte trans-endothelial migration, and cell activation by binding to integrin VLA-1 (α4β1) on T lymphocytes. VCAM-1 helps in recruitment of inflammatory cells toward tumor microenvironment and its expression is rapidly induced by proinflammatory cytokines such as TNF-α, IL-6 and TGF-β1. Overexpression of VCAM-1 along with CD44 and ABCG2 are associated with resistance to doxorubicin and cisplatin in breast cancer subjects [80-82].

MRP1, unlike MDR1, transports negatively charged naturalproduct drugs that have been modified by glutathione conjugation, glucosylation, sulfation, and glucuronylation. However, in some cases, cotransport of glutathione with positively charged drugs such as vinblastine may occur and the alteration of the cellular membrane transporters causes increased energy-dependent efflux of hydrophobic cytotoxic drugs keeping intracellular concentrations below the cell-killing threshold [74,78,82].

Variety of cancer cells showed resistant to colchicine, vinblastine, doxorubicin, vinca alkaloids, etoposide, paclitaxel, and other small molecules that are considered to be substrates for this transport system [78,82,83].

On the other hand, acquisition of drug resistance after chemotherapy is associated with increased P-gp levels that occur via specific molecular mechanisms, such as gene rearrangement. Likewise, expression of P-gp in some tumors predicts poor response to chemotherapy with drugs that are transported by P-gp [82-84].

Studies in multiple myeloma patients revealed an association between cyclin D1 gene amplification and disease severity, poor prognosis, and increased expression of MDR [85-87].

In osteosarcoma patients, the expression of the transcription factor Trps1 (trichorhinophalangeal syndrome I) is directly correlated with expression MDR1/P-gp (93). ABCB6-mediated MDR (ATP-binding cassette sub-family B member 6) is clinically relevant in some malignancies and highly expressed in breast cancer patients with detectable minimal residual disease and in patients with hepatocellular carcinoma, as opposed to a healthy liver. Also, ABCB6 is up-regulated in cell lines treated with arsenite, camptothecin, or cisplatin and cell lines of primary and secondary melanoma [88,89].

The correlation of point mutations in class III β-tubulin (TUBB3) and the prominent overexpression of ATP-binding cassette P-glycoprotein (ABCB1) have been protruding mechanisms of resistance to microtubule disruptors such as paclitaxel (PTX) for many cancers. These findings highlight the control of the TUBB3 response to ABCB1 genetic suppressors as a mechanism to reverse the profuse development of multidrug resistance in cancer.

Furthermore, the interaction between MRP1, FOXO3a, TUBB3, and PI3K/Akt signaling has been linked with doxorubicin resistance [90].

Finally, resistance to methotrexate (which is toxic folate analogs), or other nucleoside analogs commonly occurs by mutation of one or both of the folate transporters or specific mutation to the nucleoside transporters [91].

Multidrug Efflux Pumps/Resistance and Cancer Stem Like Cells (CSC): Cancer cellular heterogeneity represents a variety of cell types as well as epigenetic differences amongst the cancer cells themselves. Cancer stem like cells (CSC) is one component of this heterogeneity, which was defined by the American Association for Cancer Research (AACR) meeting in 2006 as “Self-renewable cells with pluripotency capacity to generate heterogeneous lineages of cancer cells that comprise the tumor.” However, the four major characteristics of CSCs are: self-renewing capacity; differentiation capacity; tumor-initiating capacity; and metastatic potential.

Paradoxically, the ABC efflux pumps afford protection to cancer stem cells (CSCs), shielding them from the adverse effects of chemotherapeutic insult. Hence, CSCs retains the essential property of self-protection through the activity of multiple drug resistance (MDR) transporters [92].

Current chemo-therapies of malignant tumors may eliminate the total, or near the total of the mass of malignant cells, but apparently it fails to eradicate or target the CSCs which are believed to be the cause for relapse or metastasis.

The CSC resistance may result from gene mutation, which could bepresent prior to chemotherapy, or as a result of environmental differences.

Therefore, understanding the mechanisms that regulate some traits of CSCs may help design efficient strategies to overcome chemoresistance [93].

Altered target enzyme (e.g. mutated topoisomerase II): Topoisomerase II (topo II) is a ubiquitous essential nuclear enzyme that is essential for cell survival. Topo II regulates DNA topology, DNA replication, relegates DNA fragments, modifying the linking number of a DNA loop and promotes chromosome disentanglement [94,95].

Topoisomerase II is a target of alkaloid and anthracycline agents and varieties of mutations in this gene have been associated with the development of drug resistance [96].

Topo II can be targeted by small molecules that are divided into two classes: inhibitors and poisons. The inhibitors of topoisomerase II include HU-331, ICRF-187, ICRF-193, and mitindomide. These molecules are noncompetitive inhibitors that reduce ATPase activity. Poisons of type II topoisomerases (have been extensively used as both anticancer and antibacterial therapies) include etoposide, novobiocin, quinolones (including ciprofloxacin), and teniposide. These small molecules target the DNA-protein complex leading to increased cleavage and inhibiting DNA relegation. Alteration in the enzyme function, structure, or production due to Top II mutation will impede the interaction with inhibitors and result in resistance to chemotherapy [97-99].

In triple negative breast cancer (TNBC), targeted therapies are not effective, and chemo agents currently are the main modality available for systemic therapy. Thus, the anthracyclines may be effective in treatment of TNBC as far as the topo II is not mutated [100].

Expression of T-box transcription factor T (also known as brachyury): Brachyury may attenuate cell cycle progression, enabling tumor cells to become less susceptible to radiation and chemotherapy in human carcinomas. Brachyury is a molecule frequently detected in human cancers but seldom found in normal adult tissue and has recently been characterized as a driver of the epithelial-to-mesenchymal switch of human carcinomas [100,101]. Chromatin immunoprecipitation and luciferase reporter assays revealed that Brachyury binds to a half T-box consensus site located within the promoter region of the p21 gene, indicating a potential mechanism for the observed therapeutic resistance associated with Brachyury expression [101].

Studies showed the attempts to reduce or knockdown Brachyury will reduce invasiveness, chemoresistance and radioresistance of CSCs in vivo. Therefore, Brachyury knockdown may be a useful therapeutic tool for sensitizing CSCs to conventional chemo-radiotherapy.

Also, in vitro and in vivo human lung carcinoma cells with higher levels of Brachyury divide at slower rates than those with lower levels of Brachyury, a phenomenon associated with marked downregulation of cyclin D1, phosphorylated Rb, and CDKN1A [101,102].

Non-Cellular Mechanisms

Non-cellular drug resistance is linked to the extracellular influences and is associated with unique characteristic of the tumor environment. Tumor regions that are deficient in nutrients and oxygen may reduce drug access, drug accumulation, and prevent tumor cells from cytotoxicity.

Myofibroblasts and extracellular matrix (ECM) proteins contribute to the anti-apoptotic protection of tumor cells. So, cellular adhesion molecules (e.g. L1CAM or CD44), chemokines (e.g. CXCL12), integrins, and other ECM receptors that are involved in direct and indirect interactions between tumor cells and their microenvironment have been identified as proper molecular targets to overcome chemoresistance [103].

Micro RNA and Resistant To Chemotherapy: Each micro RNA is complementary or partially complementary to one or more of mRNA molecules and its main function is to regulate the gene expression. MicroRNAs (miRNAs) are a novel class of endogenous short, non-coding RNA molecules of which the mature form is about 22 nucleotides in length. MiRNAs are counted as master regulators of gene expression by either cleaving or binding directly to its 3′-UTR region [104,105].

Several studies revealed the role of MiRNAs in chemo resistance of various malignancies and modulate multiple signaling pathways adding another mechanism of multi-drug resistance so that even subtle changes in miRNAs expression can cause significant changes in disease progression and in cancer outcomes. Depending on the cellular function of miRNAs targets, these molecules could be either an oncogene or a tumor suppressor gene [105].

Moreover, miRNAs can have opposite effects towards the same anticancer agent in different tumor types. However, the association between the effects of miRNAs and the methylation on gene expression during the progression of chemoresistance can alter the potency of various anticancer agents inversely in the same cancer cell, suggesting that the relationship between the function of miRNAs and drug resistance is highly complex [106].

Epigenetic modifications: Epigenetic modification plays a critical role during the development of acquired chemoresistance and is important in evaluating the potential application for biomarkers in cancer diagnosis as well. Epigenetics refers to the functional changes of the genome caused by methylation and/or histone post-translational modification that alters gene expression without altering the underlying DNA sequence [106,107].

DNA methylation frequently occurs in repeated sequences through the covalent addition of a methyl (CH3 ) group at the 5-carbon of the cytosine ring resulting in 5-methylcytosine [106-108]. UHRF1 (Ubiquitin-like containing PHD and RING finger domains 1) is one master regulator gene/protein in epigenetics which coordinates DNA methylation and histone modifications, which also mediates repair of damaged DNA that makes cancer cells resistant toward cytocidal drugs [109-110].

UHRF1 protein binds to specific DNA sequences and recruits DNMT1 (DNA methyltransferase 1) to regulate chromatin structure and gene expression. Its expression peaks at the late G1 phase and continues during G2 and M phases of the cell cycle. It plays a major role in the G1/S transition by regulating topoisomerase II alpha and retinoblastoma gene expressions and functions in the p53-dependent DNA damage checkpoint [111].

Therefore, the functional domains of UHRF1 utilize epigenetic inhibitory effects on TSGs including p16 with subsequent inhibition of the apoptotic pathways. It is also notable that UHRF1 regulates other TSG as observed with CDX2, CDKN2A, RUNX3, FOXO4, PPARG, BRCA1 and PLM in gastric cancer, SOCS3 and 3OST2 in endometrial carcinoma, RB1 in Jurkat and osteosarcoma cells, as well as BRCA1 in cancer breast cell lines. UHRF1 is overexpressed in colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and gastric cancer. Furthermore, its high expression level was associated with an increase in the expression of DNMT1, DNMT3A, and DNMT3B, and correlated with tumor progression and drug resistance. Hence, any agent that decreases or suppresses the expression of UHRF1/ DNMT1, as observed with natural anti-cancer drug, epigallocatechin3-gallate (EGCG), will result in cell cycle G1/S arrest and apoptosis.

In certain human cancer cell lines, the expression at the mRNA level, protein kinase activity and tumor cell anti-apoptotic activity and resistance were related to the methylation status of the caspase-8 gene promoter. Combination therapy coupled with demethylation reagents may overcome therapeutic resistance in certain malignancies [110-112].

Attempts to Overcome Resistance: In order to achieve a significant therapeutic outcome in cancers, the malignant cells need to lose their chemo protective features mediated by MRP or MDR-1, as well as enhancing the apoptotic rate of these cells.

Numerous factors could influence the ability of chemo drugs to kill cancer cells. This includes, but is not limited to, drug pharmacokinetics and metabolism; changes in microenvironment; genetic and epigenetic modifications; DNA repair genes; tumor suppressor genes; multidrug-resistance genes; apoptotic related genes; and abundant growth factors. Therefore, understanding the underlying cause of resistance is the initial step in the journey of overcoming this challenge in cancer treatment [113].

  1. As mentioned, MDR is operated by extrusion pumps, a group of ATP-binding cassette (ABC) drug transporters which include P-glycoprotein (P-gp). The P-gp overexpression in cancer cells has become a therapeutic target for bypassing MDR. One approach that has already been applied in the clinical setting has shown potentially in overcoming MDR by encapsulation of the P-gp substrate drugs in liposomes or nanoparticles [114-116].
  2. Developing anticancer drugs that are not substrates for P-gp are not susceptible to extrusion from P-gp overexpressing tumor cells. Data regarding taxanes, tesetaxel (DJ-927), and milataxel (MAC-321) shows that these drugs are poor substrates for P-gp and have demonstrated superior antitumor activity compared to docetaxel in vitro and in vivo [117-118].
  3. Overcoming resistance may be accomplished by molecules that inhibit the activity of P-gp and the efflux transporter such as telatinib or silibinin. These are natural compounds isolated from milk thistle seed extracts that inhibit ABCG2 efflux transporter activity and increase the effectiveness of drugs inside tumor cells [118,119].
  4. Inducing cell apoptosis by chemotherapy is one approach used to kill cancer cells, however, this process is often inhibited in tumor cells due to overexpression of the anti-apoptotic protein Bcl-2 or the decreased expression of pro-apoptotic proteins, such as Fas, Bax, or cysteine proteases (caspase proteins) [120-123].
  5. Overexpression of protein tyrosine kinases (PTKs), such as EGFR, HER2, and IGFR activate different cell signaling pathways that include PI3/AKT, NIFκB, STAT3, and ERK1/2, which also lead to aberrant expression apoptosis related proteins in cancer cells that are the major causes of cancer cells resistance to chemotherapies. Therefore, target therapy against specific tyrosine kinases will overcome such resistance [124]. Over years, target therapies have been developed and shown to be promising in the clinical world. Trastuzumab, an antibody that targets and binds with high affinity to the cell surface bounds HER2 receptors and prevents receptor activation [125]. Interestingly, in some conditions, resistance may evolve during time against target therapy and could be due to different mutations at a target location, multiple break points of translocations, or dysfunction in phosphorylation of proteins substrates. Hence, finding new small molecules, specific inhibitors, or combinations between target therapy and chemotherapy may prolong the progression time of breast cancer, and significantly improve survival, as opposed to chemotherapy alone [126]. On the other hand, blocking the activation of EGFR, an antibody that selectively binds EGFR-by Cetuximab, has shown to improve the response rate of 5-Fu in patients with metastatic colorectal cancer who initially failed 5-FU-based therapy [127,128].
  6. DNA methylation is an important mechanism that may lead to aberrant expression of apoptosis related genes. Then, combination of chemotherapies with agents that can reverse the methylation status is promising to overcome drug resistance [129,130].
  7. Combined chemotherapy and immunotherapy: It is promising that immunotherapy may reform the treatment of cancer by inducing, augmenting or suppressing immune responses against cancer cells, which also include monoclonal antibodies, cancer vaccines, and inhibitors of immune checkpoints such as anti PD-1/PDL-1 [131,132].
  8. Gene knockout using antisense molecules or CRISPR/Cas9 gene editing has shown to be an effective method for blocking drug resistance genes [133].
  9. Combination of autophagy inhibitors such as Chloroquine and its derivative with cytotoxic drugs is attracting more attention in cancer therapy. However, further work is needed to understand fully the functional relevance of autophagy within the tumor microenvironment and the interaction with other signaling pathways related to cancer drug resistance [134].
  10. Advancing technology for using small interfering RNA (siRNA) may create a novel treatment modality in gene-specific silencing that significantly suppresses gene expression at the messenger RNA (mRNA) and prohibit protein production [135-138]. Nevertheless, many miRs functioning as TSGs have also been shown to regulate drug sensitivity. For example, down-regulation of Let-7, miR-34, or miR-181 increases chemosensitivity, whereas down-regulation of miR-127 causes chemoresistance [139]. Overexpression of miR-125a-5p increases sensitivity to drugs, whereas overexpression of miR-15-5p is associated with drug resistance. The growing list of these miRNAs and their roles for mediating a chemotherapeutic response suggests their importance in regulating tumorigenesis and preventing cancer drug resistance [140,141]. Therefore, chemical modifications of these molecules and the use of viral vectors or nanoparticles in treatment of cancer patients may overcome this challenge.
  11. Development of small molecules target the histone modifiers such as KDM4B, may provide an opportunity to enhance the efficacy of standard chemotherapies or overcome drug resistances [142-148].


The advancement in molecular biology and in bioinformatics allows us to establish “molecular signatures” for cancer patients and identify individuals who will benefit from particular therapies.

Application of new laboratory testing such as liquid biopsy by measuring cell free RNA or cell free DNA, as well as performing sequencing of cancer genomes from FFPE tissue or from plasma, will enhance our capability to select the optimal drugs and to avoid ineffective treatment in order to accomplish the best clinical outcome.


This work was supported in part by NIH-NIMHD U54MD007598, NIH/NCI1U54CA14393, U56 CA101599-01; Department-of-Defense Breast Cancer Research Program grant BC043180, NIH/NCATS CTSI UL1TR000124 to J.V. Vadgama, and Accelerating Excellence in Translational Science Pilot Grants G0812D05, NIH/NCI SC1CA200517 to Y. Wu


  1. Fiaschi T, ChiarugiP. Oxidative stress, tumor microenvironment, and metabolic reprogramming: a diabolic liaison. J Cell Biol. 2012 Mar:762825.(Ref.)
  2. Alisi A, Cho WC, Locatelli F, Fruci D. Multidrug Resistance and Cancer Stem Cells in Neuroblastoma and Hepatoblastoma. Int J Mol Sci. 2013 Dec;14(12): 24706–24725.(Ref.)
  3. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002; 53:615-627.(Ref.)
  4. Evolution of cancer treatments: Chemotherapy. http://www.
  5. Luqmani YA. Mechanisms of drug resistance in cancer chemotherapy. Med Princ Pract. 2005;14Suppl 1:35-48.(Ref.)
  6. CTCA. United States: Cancer Treatment Centers of America. Targeted Therapy. © 2018. Available from: http://www. 2/3/2017.
  7. CTCA. United States: Cancer Treatment Centers of America. Immunotherapy. © 2018. Available from: //www.cancercenter. com/treatments/immunotherapy. 3/3/2017
  8. Fojo T, Menefee M. Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents. Ann Oncol. 2007 Jul;18 (Suppl 5): v3-v8(Ref.)
  9. Vincenzi B, Imperatori M, Silletta M, Marrucci E, Santini D, et al. Emerging kinase inhibitors of the treatment of gastric cancer. Expert Opin Emerg Drugs. 2015 May;28:1-15.(Ref.)
  10. Mead MB. Gatenby RA, Dalton WS. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer . 2009 Sep;9(9):665–674. (Ref.)
  11. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010 Mar;140(6):883-899.(Ref.)
  12. McMillin DW, Negri JM, Mitsiades CS. The role of tumourstromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Discov. 2013 Mar; 12(3):217-228.(Ref.)
  13. Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov. 2014 Dec; 13(12):928-942.(Ref.)
  14. Garnett MJ, Marais R. Guilty as charged: B-Raf is a human oncogene. Cancer Cell. 2004 Oct;6(4):313–319.(Ref.)
  15. Bian Y, Yu Y, Wang S, Li L. Up-regulation of fatty acid synthase induced by EGFR/ERK activation promotes tumor growth in pancreatic cancer. Biochem Biophys Res Commun. 2015 Aug;463(4):612-617.(Ref.)
  16. Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell. 2006;9:485-495.(Ref.)
  17. Hann CL, Brahmer JR. “Who should receive epidermal growth factor receptor inhibitors for non-small cell lung cancer and when?”. Curr Treat Options Oncol. 2007 Feb;8(1):28-37.(Ref.)
  18. Hoshi H, Hiyama G, Ishikawa K, Inageda K, Fujimoto J, et al. Construction of a novel cell-based assay for the evaluation of anti-EGFR drug efficacy against EGFR mutation. Oncol Rep. 2017 Jan;37(1):66-76.(Ref.)
  19. Jackman D, Pao W, Engelman JA, Kris MG, Jänne PA, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J ClinOncol. 2010; 28(2):357-360.(Ref.)
  20. Galvani E, Sun J, Leon LG, Sciarrillo R, Narayan RS, et al. NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor. Oncotarget. 2015 Dec;6(40):42717-42732.(Ref.)
  21. Tricker EM, Xu C, Uddin S, Capelletti M, Ercan D, et al. Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR mutant Lung Cancer. Cancer Discov. 2015 Sep;5(9):960- 971.(Ref.)
  22. Chang CC, Hsieh TL, Tiong TY, Hsiao CH, Ji AT, et al. Regulation of metastatic ability and drug resistance in pulmonary adenocarcinoma by matrix rigidity via activating c-Met and EGFR. Biomaterials. 2015 Aug;60:141-150. (Ref.)
  23. Dorantes-Heredia R, Ruiz-Morales JM, Cano-Garcia F. Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors. Transl Lung Cancer Res. 2016 Aug;5(4):401-412.(Ref.)
  24. Steelman LS, Chappell WH, Abrams SL, Kempf RC, Long J, et al. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapyimplications for cancer and aging. Aging (Albany NY). 2011 Mar; 3(3):192-222.(Ref.)
  25. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007 Jun; 129(7):1261-1274.(Ref.)
  26. Singel SM, Cornelius C, Zaganjor E, Batten K, Sarode VR, et al. KIF14 promotes AKT phosphorylation and contributes to chemoresistance in triple-negative breast cancer. Neoplasia. 2014 Mar;16(3):247-256.(Ref.)
  27. Chien-Chih Ke, Ya-Ju Hsieh, Luen Hwu, Ren-Shyan Liu, et al. Inhibition of PI3K pathway induces differentiation of anaplastic thyroid cancer and attenuates self-renewal of cancer stem cells and consequently improves the effect of radioiodidetherapy. JNucl Med. 2014; 55 (1):68.(Ref.)
  28. Carracedo A, Pandolfi PP. The PTEN–PI3K pathway: of feedbacks and cross-talks. Oncogene. 2008 Sep 18;27(41):5527-5541.(Ref.)
  29. Dillon LM, Miller TW. Therapeutic targeting of cancers with loss of PTEN function. Curr Drug Targets. 2014 Jan;15(1):65-79.(Ref.)
  30. Magee P, Shi L, Garofalo M. Role of microRNAs in chemoresistance. Ann Transl Med. 2015 Dec;3(21): 332.(Ref.)
  31. Populo H, Lopes JM, Soares P. The mTOR Signalling Pathway in Human Cancer. Int J Mol Sci. 2012; 13(2): 1886–1918. (Ref.)
  32. Xu T, Pang Q, Wang Y, Yan X. Betulinic acid induces apoptosis by regulating PI3K/Akt signaling and mitochondrial pathways in human cervical cancer cells. Int J Mol Med. 2017 Dec;40(6):1669- 1678.(Ref.)
  33. Lastwika KJ, Wilson W, Li QK, Norris J, Xu H, et al. Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. Cancer Res. 2016 Jan 15;76(2):227-238 (Ref.)
  34. Yang G, Xiao X, Rosen DG, Cheng X, Wu X, et al. The biphasic role of NF-kappaB in progression and chemoresistance of ovarian cancer. Clin Cancer Res. 2011 Apr;17(8):2181-2194(Ref.)
  35. Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, et al. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev. 2007;21(11):1396-1408.(Ref.)
  36. Godwin P, Baird AM, Heavey S, Barr MP, O’Byrne KJ, et al. Targeting Nuclear Factor-Kappa B to Overcome Resistance to Chemotherapy. Front Oncol. 2013 May; 3: 120.(Ref.)
  37. Grivennikov S, Karin M. Dangerous liaisons: STAT3 and NFkappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 2010 Feb;21(1):11-19. (Ref.)
  38. NF-κB. (Ref.)
  39. Robert M, Frenel JS, Gourmelon C, Patsouris A, Augereau P, et al. Olaparib for the treatment of breast cancer. Expert OpinInvestig Drugs. 2017 Jun;26(6):751-759.(Ref.)
  40. Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, et al. Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood. 2007 Mar;109 (6):2293-2302. (Ref.)
  41. Bierie B, Harold L. Moses HL. Transforming growth factor beta (TGF-β) and inflammation in cancer. Cytokine Growth Factor Rev. 2010 Feb;21(1):49–59.(Ref.)
  42. Takada M, Nagai S, Haruta M, Sugino RP, Tozuka K, et al. BRCA1 alterations with additional defects in DNA damage response genes may confer chemoresistance to BRCA-like breast cancers treated with neoadjuvant chemotherapy. Genes Chromosomes Cancer. 2017 May;56(5):405-420(Ref.)
  43. Lai D, Visser-Grieve S, Yang X. Tumour suppressor genes in chemotherapeutic drug response. Biosci Rep. 2012 Aug ;32(Pt 4): 361–374.(Ref.)
  44. Taylor KN, Eskander RN. PARP inhibitors in epithelial ovarian cancer. Recent Pat Anticancer Drug Discov. 2017 Dec. (Ref.)
  45. Xiao M, Cai J, Cai L, Jia J, Xie L, et al. Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair. J Ovarian Res. 2017 Apr;10(1):24.(Ref.)
  46. Xiao M, Cai J, Cai L, Jia J, Xie L, et al. Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair. J Ovarian Res. 2017 Apr;10(1):24.(Ref.)
  47. Let-7. (Ref.)
  48. RAD51.
  49. Deepthi CH, Kumar AP, Rameshbabu, Indirapriyadarshini U. Role of Tumor Suppressor Protein p53 in Apoptosis and Cancer Therapy. J Cancer Sci Ther. 2011; S17. (Ref.)
  50. Lin J, Zhang Q, Lu Y, Xue W, Xu Y, et al. Downregulation of HIPK2 increases resistance of bladder cancer cell to cisplatin by regulating Wip1. PLoS One. 2014 May;9(5):e98418. (Ref.)
  51. Bao Y, Hata Y, Ikeda M, Withanage K. Mammalian Hippo pathway: from development to cancer and beyond. J Biochem. 2011 Apr;149(4):361-379. (Ref.)
  52. Hergovich A. Mammalian Hippo signalling: a kinase network regulated by protein-protein interactions. BiochemSoc Trans. 2012 Feb;40 (1):124-128..(Ref.)
  53. Xia J, Zeng M, Zhu H, Chen X, Weng Z, et al. Emerging role of Hippo signalling pathway in bladder cancer. J Cell Mol Med. 2018 Jan;22(1):4-15.(Ref.)
  54. Ercolani C, Di Benedetto A, Terrenato I, Pizzuti L, Di Lauro L, et al. Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy. Cancer BiolTher. 2017 May;18(5):339-346. (Ref.)
  55. Xie C, Han Y, Fu L, Li Q, Qiu X, et al. Overexpression of CARMA3 is associated with advanced tumor stage, cell cycle progression, and cisplatin resistance in human epithelial ovarian cancer. Tumour Biol. 2014 Aug; 35(8):7957-7964.(Ref.)
  56. Wiltshire T, Senft J, Wang Y, Konat GW, Wenger SL, et al. BRCA1 contributes to cell cycle arrest and chemoresistance in response to the anticancer agent irofulven. MolPharmacol. 2007 Apr;71(4):1051-1060.(Ref.)
  57. Sun B, Fang Y, Li Z, Chen Z, Xiang J. Role of cellular cytoskeleton in epithelial-mesenchymal transition process during cancer progression. Biomed Rep. 2015 Sep; 3(5): 603–610. (Ref.)
  58. Chacón-Martínez CA, Kiessling N, Winterhoff M, Faix J, MüllerReichert T, et al. The Switch-associated Protein 70 (SWAP-70) Bundles Actin Filaments and Contributes to the Regulation of F-actin Dynamics. J Biol Chem. 2013 Oct; 288(40): 28687– 28703. (Ref.)
  59. Kohrman AQ, Matus DQ. Divide or Conquer: Cell Cycle Regulation of Invasive Behavior. Trends Cell Biol. 2017 Jan;27(1):12-25.(Ref.)
  60. Li J, Poi MJ, Tsai MD. The Regulatory Mechanisms of Tumor Suppressor P16INK4A and Relevance to Cancer. Biochemistry. 2011 Jun; 50(25): 5566–5582.(Ref.)
  61. Zhou J, Wang Y, Wang Y, Yin X, He Y, et al. FOXM1 modulates cisplatin sensitivity by regulating EXO1 in ovarian cancer. PLoS One. 2014 May; 9(5):e96989. (Ref.)
  62. Ma X, Chen Z, Hua D, He D, Wang L, et al. Essential role for TrpC5-containing extracellular vesicles in breast cancer with chemotherapeutic resistance. Proc Natl AcadSci U S A. 2014;111(17):6389-6394.(Ref.)
  63. Mastropasqua F, Marzano F, Valletti A, Aiello I, Di Tullio G, et al. TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours. Mol Cancer. 2017 Mar;16(1):67.(Ref.)
  64. Wang L, Liu X, Ren Y, Zhang J, Chen J, et al. Cisplatin-enriching cancer stem cells confer multidrug resistance in non-small cell lung cancer via enhancing TRIB1/HDAC activity. Cell Death Dis. 2017 Apr;8(4):e2746. (Ref.)
  65. Gong Z, Sun P, Chu H, Zhu H, Sun D. Overexpression of sorcin in multidrug-resistant human breast cancer. Oncol Lett. 2014 Dec;8(6):2393-2398.(Ref.)
  66. Maddalena F, Laudiero G, Piscazzi A, Secondo A, Scorziello A, et al. Sorcin Induces a Drug-Resistant Phenotype in Human Colorectal Cancer by Modulating Ca2þ Homeostasis. Therapeutics, Targets, and Chemical Biology. Cancer Res. 2011 Dec 15;71(24):7659- 7669.(Ref.)
  67. Hayden A, Douglas J, Sommerlad M, Andrews L, Gould K, et al. The Nrf2 transcription factor contributes to resistance to cisplatin in bladder cancer. UrolOncol. 2014 Aug; 32(6):806-814.(Ref.)
  68. Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 2008 Jun;29(6):1235- 1243.(Ref.)
  69. Kawata H, Kamiakito T, Nakaya T, Komatsubara M, Komatasu K, et al. Stimulation of cellular senescent processes, including secretory phenotypes and anti-oxidant responses, after androgen deprivation therapy in human prostate cancer. J Steroid BiochemMol Biol. 2017 Jan;165(Pt B):219-227.(Ref.)
  70. Mishra DK, Chen Z, Wu Y, Sarkissyan M, Koeffler HP, et al. Global methylation pattern of genes in androgen-sensitive and androgen-independent prostate cancer cells. Mol Cancer Ther. 2010; 9(1):33-45.(Ref.)
  71. Mimeault M, Batra SK. Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J Cell Mol Med. 2013 Jan;17(1):30-54.(Ref.)
  72. Raz S, Sheban D, Gonen N, Stark M, Berman B, et al. Severe hypoxia induces complete antifolate resistance in carcinoma cells due to cell cycle arrest. Cell Death Dis. 2014 Feb;5:e1067. (Ref.)
  73. Gagner JP, Sarfraz Y, Ortenzi V, Alotaibi FM, Chiriboga LA, et al. Multifaceted C-X-C Chemokine Receptor 4 (CXCR4) Inhibition Interferes with Anti-Vascular Endothelial Growth Factor Therapy-Induced Glioma Dissemination. Am J Pathol. 2017 Sep;187(9):2080-2094.(Ref.)
  74. Szakacs G, Annereau JP, Lababidi S, Shankavaram U, Arciello A, et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell. 2004;6:129–137. (Ref.)
  75. Multidrug resistance-associated protein 2. http://en.wikipedia. org/wiki/Multidrug_resistance-associated_protein.
  76. P-glycoprotein.
  77. Zahreddine H, Borden KL. Mechanisms and insights into drug resistance in cancer. Front Pharmacol. 2013 Mar 14;4:28.(Ref.)
  78. Mirzaei SA, GholamianDehkordi N, Ghamghami M, Amiri AH, DalirAbdolahinia E, et al. ABC-transporter blockage mediated by xanthotoxin and bergapten is the major pathway for chemosensitization of multidrug-resistant cancer cells. Toxicol Appl Pharmacol. 2017 Dec;337:22-29. (Ref.)
  79. Yamagishi N, Nakao R, Kondo R, Nishitsuji M, Saito Y, et al. Increased expression of sorcin is associated with multidrug resistance in leukemia cells via up-regulation of MDR1 expression through cAMP response element-binding protein. Biochem Biophys Res Commun. 2014 Jun;448(4):430-436. (Ref.)
  80. Wang PC, Weng CC, Hou YS, Jian SF, Fang KT, et al. Activation of VCAM-1 and Its Associated Molecule CD44 Leads to Increased Malignant Potential of Breast Cancer Cells. Int J Mol Sci. 2014 March; 15(3): 3560–3579.(Ref.)
  81. Panettieri, RA Jr, Lazaar AL, Pure, E.; Albelda, S.M. Activation of cAMP-dependent pathways in human airway smooth muscle cells inhibits TNF-α-induced ICAM-1 and VCAM-1 expression and T lymphocyte adhesion. J Immunol. 1995;154(5):2358– 2365.(Ref.)
  82. Taheri M, Mahjoubi F. MRP1 but not MDR1 is associated with response to neoadjuvant chemotherapy in breast cancer patients. Dis Markers. 2013;34(6):387-93. (Ref.)
  83. Shukla S, Ohnuma S, Ambudkar SV. Improving cancer chemotherapy with modulators of ABC drug transporters. Curr Drug Targets. 2011 May;12(5): 621-630.(Ref.)
  84. Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017 Nov;551:247–250.(Ref.)
  85. Sewify EM, Afifi OA, Mosad E, Zaki AH, El Gammal SA. Cyclin D1 amplification in multiple myeloma is associated with multidrug resistance expression. Clin Lymphoma Myeloma Leuk. 2014 Jun;14(3):215-222(Ref.)
  86. Heimerl S, Bosserhoff AK, Langmann T, Ecker J, Schmitz G. Mapping ATP-binding cassette transporter gene expression profiles in melanocytes and melanoma cells. Melanoma Res 2007 Oct; 17(5):265–273. (Ref.)
  87. Zhou W, Yang Y, Xia J, Wang H, Salama ME, et al. NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers. Cancer Cell. 2013 Jan 14;23(1):48-62.(Ref.)
  88. Jia M, Hu J, Li W, Su P, Zhang H, et al. Trps1 is associated with the multidrug resistance of osteosarcoma by regulating MDR1 gene expression. FEBS Lett. 2014 Mar;588(5):801-810.(Ref.)
  89. Paterson JK, Shukla S, Black CM, Tachiwada T, Garfield S, et al. Human ABCB6 localizes to both the outer mitochondrial membrane and the plasma membrane. Biochemistry 2007 Aug; 46:9443–9452.(Ref.)
  90. Aldonza MB, Hong JY, Alinsug MV, Song J, Lee SK. Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation. Oncotarget. 2016 Jun ;7(23):34395-34419.(Ref.)
  91. Cheung A, Bax HJ, Josephs DH, Ilieva KM, Pellizzari G, et al. Targeting folate receptor alpha for cancer treatment. Oncotarget. 2016 Aug;7(32): 52553–52574.(Ref.)
  92. Moitra K. Overcoming Multidrug Resistance in Cancer Stem Cells. Biomed Res Int. 2015; 2015: 635745.(Ref.)
  93. Garg M. Epithelial plasticity and cancer stem cells: Major mechanisms of cancer pathogenesis and therapy resistance. World J Stem Cells. 2017 Aug;9(8):118-126. (Ref.)
  94. Type II topoisomerase. topoisomerase. 9/5/2017.
  95. Beck WT, Danks MK. Mechanisms of resistance to drugs that inhibit DNA topoisomerases. Semin Cancer Biol. 1991 Aug;2(4):235-244.(Ref.)
  96. Leontiou C, Lakey JH, Austin CA. Mutation E522K in human DNA topoisomerase IIbeta confers resistance to methyl N-(4’- (9-acridinylamino)-phenyl)carbamate hydrochloride and methyl N-(4’-(9-acridinylamino)-3-methoxy-phenyl) methane sulfonamide but hypersensitivity to etoposide. Mol Pharmacol. 2004 Sep; 66(3):430-439. (Ref.)
  97. Bau JT, Kang Z, Austin CA, Kurz EU. Salicylate, a catalytic inhibitor of topoisomerase II, inhibits DNA cleavage and is selective for the αisoform. Mol Pharmacol. 2014 Feb;85(2):198-207.(Ref.)
  98. Hofmann GA, Mattern MR. Topoisomerase II in multiple drug resistance. Cytotechnology. 1993;12(1-3):137-154(Ref.)
  99. Mrklic I, Pogorelic Z, Capkun V, Tomic S. Expression of topoisomerase II-α in triple negative breast cancer. Appl Immunohistochem Mol Morphol. 2014 Mar;22(3):182-187.(Ref.)
  100. Palena C, Fernando R, Hamilton DH. An immunotherapeutic intervention against tumor progression: Targeting a driver of the epithelial-to-mesenchymal transition. Oncoimmunology. 2014 Jan; 3(1):e27220.(Ref.)
  101. . Huang B, Cohen JR, Fernando RI, Hamilton DH, Litzinger MT, et al. The embryonic transcription factor Brachyury blocks cell cycle progression and mediates tumor resistance to conventional antitumor therapies. Cell Death Dis. 2013 Jun;4:e682.(Ref.)
  102. Kobayashi Y, Sugiura T, Imajyo I, Shimoda M, Ishii K, et al. Knockdown of the T-box transcription factor Brachyury increases sensitivity of adenoid cystic carcinoma cells to chemotherapy and radiation in vitro: implications for a new therapeutic principle. Int J Oncol. 2014 Apr; 44(4):1107-1117.(Ref.)
  103. Sebens S, Schafer H. The tumor stroma as mediator of drug resistance--a potential target to improve cancer therapy? Curr Pharm Biotechnol. 2012 Sep;13(11):2259-2272.(Ref.)
  104. . Felekkis K, Touvana E, Stefanou Ch, Deltas C. microRNAs: a newly described class of encoded molecules that play a role in health and disease. Hippokratia. 2010 Oct;14(4): 236–240.(Ref.)
  105. Sokilde R, Kaczkowski B, Podolska A, Cirera S, Gorodkin J, et al. Global microRNA analysis of the NCI-60 cancer cell panel. Mol Cancer Ther. 2011 Mar;10:375-384.(Ref.)
  106. . van Beijnum JR, Giovannetti E, Poel D, Nowak-Sliwinska P, Griffioen AW. miRNAs: micro-managers of anticancer combination therapies. Angiogenesis. 2017 May;20(2):269-285. (Ref.)
  107. DNA Methylation. 10/2/2017.
  108. Epigenetics. 3/14/2017.
  109. Mummaneni P, Shord SS. Epigenetics and Oncology. Pharmacotherapy. 2014 May;34(5):495-505.(Ref.)
  110. UHRF1. 11/23/2017.(Ref.)
  111. Alhosin M, Omran Z, Zamzami MA, Al-Malki AL, Choudhry H, et al. Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer. J Exp Clin Cancer Res. 2016 Nov 14;35(1):174.(Ref.)
  112. . Sidhu H, Capalash N. UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics. Tumour Biol. 2017 Feb;39(2).(Ref.)
  113. Liu X, Gao Q, Li P, Zhao Q, Zhang J, et al. UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi-methylated DNA and methylated H3K9. Nat Commun. 2013;4:1563.(Ref.)
  114. Onda K, Suzuki R, Tanaka S, Oga H, Oka K, et al. Decitabine, a DNA methyltransferase inhibitor, reduces P-glycoprotein mRNA and protein expressions and increases drug sensitivity in drugresistant MOLT4 and Jurkat cell lines. Anticancer Res. 2012 Oct; 32(10):4439-4444.(Ref.)
  115. Nobili S, Landini I, Giglioni B, Mini E. Pharmacological strategies for overcoming multidrug resistance. Curr Drug Targets 2006; 7:861–879.(Ref.)
  116. Dong X, Mumper RJ. Nanomedicinal strategies to treat multidrugresistant tumors: current progress. Nanomedicine (Lond). 2010 Jun; 5(4): 597–615.(Ref.)
  117. Esser L, Zhou F, Pluchino KM, Shiloach J, Ma J, et al. Structures of the Multidrug Transporter P-glycoprotein Reveal Asymmetric ATP Binding and the Mechanism of Polyspecificity. J Biol Chem. 2017 Jan 13; 292(2): 446–461. (Ref.)
  118. Janet L. Markman1 Arthur RekechenetskiyEggehard Holler Julia Y.Ljubimova. Nanomedicine therapeutic approaches to overcome cancer drug resistance.Advanced Drug Delivery Reviews. Volume 65, Issues 13–14, 30 November 2013, Pages 1866-1879.(Ref.)
  119. Shukla S, Wu CP, Ambudkar SV. Development of inhibitors of ATP-binding cassette drug transporters: Present status and challenges. Expert Opin Drug MetabToxicol. 2008 Feb;4(2):205- 223.(Ref.)
  120. Flores JP, Saif MW. Novel oral taxane therapies: recent Phase I results. Clin Investig. 2013;3(4): 333–341.(Ref.)
  121. Shionoya M, Jimbo T, Kitagawa M, Soga T, Tohgo A. DJ-927, a novel oral taxane, overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivo. Cancer Sci. 2003 May;94(5):459- 466. (Ref.)
  122. Sampath D, Discafani CM, Loganzo F, Beyer C, Liu H, et al. MAC321, a novel taxane with greater efficacy than paclitaxel and docetaxel in vitro and in vivo. Mol Cancer Ther. 2003; 2:873–884.(Ref.)
  123. Sodani K, Patel A, Anreddy N, Singh S, Yang DH, et al. Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo. ZS3. BiochemPharmacol. 2014 May; 89(1):52-61.(Ref.)
  124. Noori-Daloii MR, Saffari M, Raoofian R, Yekaninejad M, Dinehkabodi OS, et al. The multidrug resistance pumps are inhibited by silibinin and apoptosis induced in K562 and KCL22 leukemia cell lines. Leuk Res. 2014 May; 38(5):575-580.(Ref.)
  125. Teng Y, Dong YC, Liu Z, Zou Y, Xie H, et al. DNA methylationmediated caspase-8 downregulation is associated with antiapoptotic activity and human malignant glioma grade. Int J Mol Med. 2017 Mar;39(3):725-733.(Ref.)
  126. . Bonetti A, Zaninelli M, Leone R, Cetto GL, Pelosi G, et al. bcl2 but not p53 expression is associated with resistance to chemotherapy in advanced breast cancer. Clin Cancer Res. 1998; 4(10): 2331–2336. (Ref.)
  127. Krajewski S, Blomqvist C, Franssila K, Krajewska M, Wasenius VM, et al. Reduced expression of pro-apoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. Cancer Res. 1995 Oct 1;55(19):4471- 4478. (Ref.)
  128. Wu Y, Alvarez M, Slamon DJ, Koeffler P, Vadgama JV. Caspase 8 and maspin are downregulated in breast cancer cells due to CpG site promoter methylation. BMC Cancer. 2010 Feb 4;10:32.(Ref.)
  129. Xia P, Xu XY. PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application. Am J Cancer Res. 2015; 5(5): 1602–1609.(Ref.)
  130. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–372.(Ref.)
  131. Johnson DH. Targeted therapies in combination with chemotherapy in non-small cell lung cancer. Cancer Res. 2006 Jul 15;12(14 Pt 2):4451s-4457s. (Ref.)
  132. Reid TE, Fortunak JM, Wutoh A, Simon Wang X. Cheminfomaticbased Drug Discovery of Human Tyrosine Kinase Inhibitors. Curr Top Med Chem. 2016; 16(13): 1452–1462.(Ref.)
  133. Wee P, Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers (Basel) 2017 May; 9(5): 52.(Ref.)
  134. Issa ME, Takhsha FS, Chirumamilla CS, Perez-Novo C, Vanden Berghe W, et al. Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma. Clinical Epigenetics. 20179:17. (Ref.)
  135. Zeller C. Therapeutic modulation of epigenetic drivers of drug resistance in ovarian cancer. TherAdv Med Oncol. 2010 Sep; 2(5): 319–329. (Ref.)
  136. Emens LA, Middleton G. The Interplay of Immunotherapy and Chemotherapy: Harnessing Potential Synergies. Cancer Immunol Res. 2015 May; 3(5): 436-443.(Ref.)
  137. Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, et al. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front Pharmacol. 2017; 8: 561. (Ref.)
  138. Chira S, Gulei D, Hajitou A, Zimta AA, Cordelier P. CRISPR/Cas9: Transcending the Reality of Genome Editing. Mol Ther Nucleic Acids. 2017 Jun;7: 211–222. (Ref.)
  139. Sui X, Chen R, Wang Z, Huang Z, Kong N, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013 Oct; 4(10): e838.(Ref.)
  140. Pai SI, Lin YY, Macaes B, Meneshian A, Hung CF, et al. Prospects of RNA interference therapy for cancer. Gene Ther. 2006 Mar;13(6):464-477.(Ref.)
  141. Xu C, Wang J. Delivery systems for siRNA drug development in cancer therapy. Asian Journal of Pharmaceutical Sciences. 2015 Feb;10(1): 1-12. (Ref.)
  142. Young SW, Stenzel M, Yang JL. Nanoparticle-siRNA: A potential cancer therapy? Crit Rev Oncol Hematol. 2016 Feb;98:159-169. (Ref.)
  143. Mirzaei H, Yazdi F, Salehi R, Mirzaei HR. SiRNA and epigenetic aberrations in ovarian cancer. J Cancer Res Ther. 2016 AprJun;12(2):498-508.(Ref.)
  144. Hummel R, Hussey DJ, Haier J. MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types. Eur J Cancer. 2010 Jan;46(2):298-311. (Ref.)
  145. Zhong L, Sun S, Shi J, Cao F, Han X, et al. MicroRNA-125a-5p plays a role as a tumor suppressor in lung carcinoma cells by directly targeting STAT3. Tumour Biol. 2017 Jun;39(6).(Ref.)
  146. . Chen Y, Lian YJ, Ma YQ, Wu CJ, Zheng YK, et al. LncRNA SNHG1 promotes α-synuclein aggregation and toxicity by targeting miR15b-5p to activate SIAH1 in human neuroblastoma SH-SY5Y cells. Neurotoxicology. 2017 Dec; S0161-813X(17)30235-8.(Ref.)
  147. Wang J, Wang H, Wang LY, Cai D, Duan Z, et al. Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy. Cell Death Differ. 2016 Nov;23(11):1886-1896.(Ref.)
  148. Chu CH, Wang LY, Hsu KC, Chen CC, Cheng HH, et al. KDM4B as a target for prostate cancer: structural analysis and selective inhibition by a novel inhibitor. J Med Chem. 2014 Jul;57(14):5975-5985.(Ref.)
  149. Lapinska K, Housman G, Byler S, Heerboth S, Willbanks A, et al. The Effects of Histone Deacetylase Inhibitor and Calpain Inhibitor Combination Therapies on Ovarian Cancer Cells. Anticancer Res. 2016 Nov;36(11):5731-5742.(Ref.)