Genetic Variants Involved in Intracellular Mechanisms of Chemoresistance to Anticancer Drugs Due to Changes in the Effect on Their Molecular Targets


Modern anticancer pharmacological treatment is challenged by the important limitation of the refractoriness of many tumours to anticancer drugs. This is due to different combinations of a complex and yet poorly understood variety of mechanisms of chemoresistance, which account for a reduction in the intracellular concentrations of active agents or poor response to their action. The present article focusses on changes in the expression and appearance of the genetic variants affecting genes involved in a weaker activity of the intracellular active agents, which may be accounted for by: (1) changes in the molecular targets of these drugs, either by directly reducing or enhancing the expression of the target or by modifying its ability to respond to the drug; (2) enhanced repair of drug‐induced deoxyribonucleic acid damage; and finally, because the activation of apoptosis is a final goal of many pharmacological regimes; (3) the stimulation of antiapoptotic mechanisms and/or the inhibition of proapoptotic ones.

Key Concepts:

  • Changes in the expression levels of molecular targets strongly determine the efficacy of anticancer drugs.

  • Chemoresistance may be due to the appearance of genetic variants accounting for changes in the ability of molecular targets to respond to anticancer drugs.

  • Antitumour drugs, whose mechanism of action is based on DNA damage, are less efficient in tumour cells with enhanced DNA‐repairing activity.

  • The presence of genetic variants accounting for an impaired function of proapoptotic genes favour tumour chemoresistance.

  • The presence of genetic variants accounting for a constitutive activation of survival pathways reduces the efficacy of anticancer drugs.

Keywords: apoptosis; anticancer drug; cancer; mutation; pharmacology; refractoriness; SNP

Figure 1.

Schematic representation of genes involved in MOC due to changes of expression or the appearance of genetic variants in the molecular targets of anticancer drugs.



Antonescu CR, Besmer P, Guo T et al. (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clinical Cancer Research 11(11): 4182–4190.

Batra SK, Castelino‐Prabhu S, Wikstrand CJ et al. (1995) Epidermal growth factor ligand‐independent, unregulated, cell‐transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth & Differentiation 6(10): 1251–1259.

Bepler G, Williams C, Schell MJ et al. (2013) Randomized international phase III trial of ERCC1 and RRM1 expression‐based chemotherapy versus gemcitabine/carboplatin in advanced non‐small‐cell lung cancer. Journal of Clinical Oncology 31(19): 2404–2412.

Bradbury PA, Kulke MH, Heist RS et al. (2009) Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes. Pharmacogenetics and Genomics 19(8): 613–625.

Chahardouli B, Zaker F, Mousavi SA et al. (2013) Detection of BCR‐ABL kinase domain mutations in patients with chronic myeloid leukemia on imatinib. Hematology 18(6): 328–333.

Chen C, Wang F, Wang Z et al. (2013) Polymorphisms in ERCC1 C8092A predict progression‐free survival in metastatic/recurrent nasopharyngeal carcinoma treated with cisplatin‐based chemotherapy. Cancer Chemotherapy and Pharmacology 72(2): 315–322.

Cho Y, Gorina S, Jeffrey PD and Pavletich NP (1994) Crystal structure of a p53 tumor suppressor‐DNA complex: understanding tumorigenic mutations. Science 265(5170): 346–355.

Debatin KM and Krammer PH (2004). Death receptors in chemotherapy and cancer. Oncogene 23(16): 2950–2966.

Di Nicolantonio F, Martini M, Molinari F et al. (2008) Wild‐type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. Journal of Clinical Oncology 26(35): 5705–5712.

Duan H, Heckman CA and Boxer LM (2007) The immunoglobulin heavy‐chain gene 3′ enhancers deregulate bcl‐2 promoter usage in t(14;18) lymphoma cells. Oncogene 26(18): 2635–2641.

Fujimoto A, Takeuchi H, Taback B et al. (2004) Allelic imbalance of 12q22‐23 associated with APAF‐1 locus correlates with poor disease outcome in cutaneous melanoma. Cancer Research 64(6): 2245–2250.

Galvani E, Alfieri R, Giovannetti E et al. (2013) Epidermal growth factor receptor tyrosine kinase inhibitors: current status and future perspectives in the development of novel irreversible inhibitors for the treatment of mutant non‐small cell lung cancer. Current Pharmaceutical Design 19(5): 818–832.

Giachino DF, Ghio P, Regazzoni S et al. (2007) Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer. Clinical Cancer Research 13(10): 2876–2881.

Gourdier I, Del Rio M, Crabbe L et al. (2002) Drug specific resistance to oxaliplatin is associated with apoptosis defect in a cellular model of colon carcinoma. FEBS Letters 529(2–3): 232–236.

Gurubhagavatula S, Liu G, Park S et al. (2004) XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non‐small‐cell lung cancer patients treated with platinum chemotherapy. Journal of Clinical Oncology 22(13): 2594–2601.

Heinrich MC, Corless CL, Demetri GD et al. (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. Journal of Clinical Oncology 21(23): 4342–4349.

Hu G, Chong RA, Yang Q et al. (2009) MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor‐prognosis breast cancer. Cancer Cell 15(1): 9–20.

Karpova MB, Schoumans J, Blennow E et al. (2006) Combined spectral karyotyping, comparative genomic hybridization, and in vitro apoptyping of a panel of Burkitt's lymphoma‐derived B cell lines reveals an unexpected complexity of chromosomal aberrations and a recurrence of specific abnormalities in chemoresistant cell lines. International Journal of Oncology 28(3): 605–617.

Kim DH, Xu W, Kamel‐Reid S et al. (2010) Clinical relevance of vascular endothelial growth factor (VEGFA) and VEGF receptor (VEGFR2) gene polymorphism on the treatment outcome following imatinib therapy. Annals of Oncology 21(6): 1179–1188.

Lecomte T, Ferraz JM, Zinzindohoue F et al. (2004) Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5‐fluorouracil‐based chemotherapy. Clinical Cancer Research 10(17): 5880–5888.

Lee JH, Soung YH, Lee JW et al. (2004) Inactivating mutation of the pro‐apoptotic gene BID in gastric cancer. Journal of Pathology 202(4): 439–445.

Lee MH, Lee SE, Kim DW et al. (2011) Mitochondrial localization and regulation of BRAFV600E in thyroid cancer: A clinically used RAF inhibitor is unable to block the mitochondrial activities of BRAFV600E. Journal of Clinical Endocrinology and Metabolism 96(1): E19–E30.

Liu XJ, Wu WT, Wu WH et al. (2013) A minority subpopulation of CD133 /EGFRvIII /EGFR cells acquires stemness and contributes to Gefitinib resistance. CNS Neuroscience & Therapeutics 19(7): 494–502.

Ma Y, Zeng S, Metcalfe DD et al. (2002) The c‐KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild‐type kinases and those with regulatory‐type mutations. Blood 99(5): 1741–1744.

Marin JJ, Briz O, Monte MJ, Blazquez AG and Macias RI (2012) Genetic variants in genes involved in mechanisms of chemoresistance to anticancer drugs. Current Cancer Drug Targets 12(4): 402–438.

Marin JJ, Romero MR, Martinez‐Becerra P, Herraez E and Briz O (2009) Overview of the molecular bases of resistance to chemotherapy in liver and gastrointestinal tumours. Current Molecular Medicine 9(9): 1108–1129.

Ohno H and Isoda K (2008) t(11;18)(q21;q21)‐positive advanced‐stage MALT lymphoma associated with monoclonal gammopathy: resistance to rituximab or rituximab‐containing chemotherapy. Journal of Clinical and Experimental Hematopathology 48(2): 47–54.

Olejniczak SH, Hernandez‐Ilizaliturri FJ, Clements JL and Czuczman MS (2008) Acquired resistance to rituximab is associated with chemotherapy resistance resulting from decreased Bax and Bak expression. Clinical Cancer Research 14(5): 1550–1560.

Ory K, Legros Y, Auguin C and Soussi T (1994) Analysis of the most representative tumour‐derived p53 mutants reveals that changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation. EMBO Journal 13(15): 3496–3504.

Park DJ, Zhang W, Stoehlmacher J et al. (2003) ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal cancer patients treated with platinum‐based chemotherapy. Clinical Advances in Hematology and Oncology 1(3): 162–166.

Petitjean A, Mathe E, Kato S et al. (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Human Mutation 28(6): 622–629.

Quintas‐Cardama A and Verstovsek S (2013) Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clinical Cancer Research 19(8): 1933–1940.

Rampino N, Yamamoto H, Ionov Y et al. (1997) Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275(5302): 967–969.

Ryu JS, Hong YC, Han HS et al. (2004) Association between polymorphisms of ERCC1 and XPD and survival in non‐small‐cell lung cancer patients treated with cisplatin combination chemotherapy. Lung Cancer 44(3): 311–316.

Sacerdote C, Guarrera S, Ricceri F et al. (2013) Polymorphisms in the XRCC1 gene modify survival of bladder cancer patients treated with chemotherapy. International Journal of Cancer 133(8): 2004–2009.

Samuels Y, Diaz LA Jr, Schmidt‐Kittler O et al. (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7(6): 561–573.

Scheffzek K, Ahmadian MR, Kabsch W et al. (1997) The Ras‐RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277(5324): 333–338.

Schindler T, Bornmann W, Pellicena P et al. (2000) Structural mechanism for STI‐571 inhibition of abelson tyrosine kinase. Science 289(5486): 1938–1942.

Shah NP, Nicoll JM, Nagar B et al. (2002) Multiple BCR‐ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2(2): 117–125.

Soussi T and Beroud C (2001) Assessing TP53 status in human tumours to evaluate clinical outcome. Nature Reviews Cancer 1(3): 233–240.

Todd JR, Becker TM, Kefford RF and Rizos H (2013) Secondary c‐Kit mutations confer acquired resistance to RTK inhibitors in c‐Kit mutant melanoma cells. Pigment Cell & Melanoma Research 26(4): 518–526.

Villa E, Dugani A, Fantoni E et al. (1996) Type of estrogen receptor determines response to antiestrogen therapy. Cancer Research 56(17): 3883–3885.

Wagner KW, King F, Nomoto K et al. (2003) Activation and suppression of the TRAIL death‐receptor pathway in chemotherapy sensitive and resistant follicular lymphoma cells. Cancer Biology and Therapy 2(5): 534–540.

Wang H, Jiang H, Zhou M et al. (2009) Epidermal growth factor receptor vIII enhances tumorigenicity and resistance to 5‐fluorouracil in human hepatocellular carcinoma. Cancer Letters 279(1): 30–38.

Yoo BK, Emdad L, Su ZZ et al. (2009) Astrocyte elevated gene‐1 regulates hepatocellular carcinoma development and progression. Journal of Clinical Investigation 119(3): 465–477.

Yu D, Shi J, Sun T et al. (2012) Pharmacogenetic role of ERCC1 genetic variants in treatment response of platinum‐based chemotherapy among advanced non‐small cell lung cancer patients. Tumor Biology 33(3): 877–884.

Zhou C, Ren S, Zhou S et al. (2010) Predictive effects of ERCC1 and XRCC3 SNP on efficacy of platinum‐based chemotherapy in advanced NSCLC patients. Japanese Journal of Clinical Oncology 40(10): 954–960.

Further Reading

Bowen ID (1999) Apoptosis and cancer chemotherapy. Cell Biology International 23(11): 794. Doi: 10.1006/cbir.1999.0464.

Conesa-Zamora P, Garcia-Solano J, Garcia-Garcia F et al. (2013) Expression profiling shows differential molecular pathways and provides potential new diagnostic biomarkers for colorectal serrated adenocarcinoma. International Journal of Cancer 132(2): 297–307.

Herraez E, Gonzalez-Sanchez E, Vaquero J et al. (2012) Cisplatin‐induced chemoresistance in colon cancer cells involves FXR‐dependent and FXR‐independent up‐regulation of ABC proteins. Molecular Pharmacology 9(9): 2565–2576.

Marin JJ, Castano B, Blazquez AG et al. (2010) Strategies for overcoming chemotherapy resistance in enterohepatic tumours. Current Molecular Medicine 10(5): 467–485.

Marin JJ, Sanchez de Medina F, Castano B et al. (2012) Chemoprevention, chemotherapy, and chemoresistance in colorectal cancer. Drug Metabolism Reviews 44(2): 148–172.

Martinez‐Becerra P, Monte I, Romero MR et al. (2012) Up‐regulation of FXR isoforms is not required for stimulation of the expression of genes involved in the lack of response of colon cancer to chemotherapy. Pharmacological Research 66(5): 419–427.

Martinez‐Becerra P, Vaquero J, Romero MR et al. (2012) No correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors. Molecular Pharmacology 9(6): 1693–1704.

Matthews DJ and Gerritsen ME (2010) Targeting Protein Kinases for Cancer Therapy. Hoboken, NJ: Wiley.

Shortt J and Johnstone RW (2012) Oncogenes in cell survival and cell death. Cold Spring Harbor Perspectives in Biology 4(12): a009829. doi: 10.1101/cshperspect.a009829.

Tiwari M (2012) Antimetabolites: established cancer therapy. Journal of Cancer Research and Therapeutics 8(4): 510–519.

Vaquero J, Briz O, Herraez E, Muntane J and Marin JJ (2013) Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds. Biochimica et Biophysica Acta 1833(10): 2212–2219.

Weng L, Zhang L, Peng Y and Huang RS (2013) Pharmacogenetics and pharmacogenomics: a bridge to individualized cancer therapy. Pharmacogenomics 14(3): 315–324.

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Marin, Jose JG, Blazquez, Alba G, Serrano, Maria A, Briz, Oscar, Monte, Maria J, and Macias, Rocio IR(Dec 2013) Genetic Variants Involved in Intracellular Mechanisms of Chemoresistance to Anticancer Drugs Due to Changes in the Effect on Their Molecular Targets. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025217]