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Cancer drug resistance: an evolving paradigm

Key Points

  • Tumour resistance to chemotherapy and molecularly targeted therapies limits the effectiveness of current cancer therapies.

  • Toxicity to normal tissues limits the amount of drug that can be systemically administered, and pharmacokinetic effects (absorption, distribution, metabolism and elimination (ADME)) limit the amount of drug that reaches the tumour.

  • At the level of the tumour, various resistance mechanisms can operate, such as increased drug efflux, mutations of the drug target, DNA damage repair, activation of alternative signalling pathways and evasion of cell death.

  • Tumour resistance can be intrinsic (that is, present before treatment), or acquired during treatment by various therapy-induced adaptive responses.

  • Tumours are heterogeneous; therefore, resistance can also arise by positive selection of a drug-resistant tumour subpopulation.

  • High-throughput screening techniques and systems biology approaches have the power to identify novel mechanisms of drug resistance and molecular signatures and genotypes that predict tumour response.

  • Increasingly, predictive biomarkers will be used clinically to stratify patients to receive specific therapeutics.

  • Improved understanding of the molecular basis of resistance will inevitably lead to the clinical assessment of rational drug combinations in selected patient populations.

Abstract

Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.

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Figure 1: General principles of drug resistance.
Figure 2: Summary of downstream factors that influence drug resistance.
Figure 3: Apoptosis signalling and therapeutic targeting.
Figure 4: Mechanisms of resistance to molecularly targeted therapies as exemplified by EGFR, RAF and MEK inhibitors.

References

  1. Longley, D. B. & Johnston, P. G. Molecular mechanisms of drug resistance. J. Pathol. 205, 275–292 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Swanton, C. Intratumor heterogeneity: evolution through space and time. Cancer Res. 72, 4875–4882 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gottesman, M. M., Fojo, T. & Bates, S. E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nature Rev. Cancer 2, 48–58 (2002).

    Article  CAS  Google Scholar 

  4. Borst, P. & Elferink, R. O. Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 71, 537–592 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Fojo, T. & Bates, S. Strategies for reversing drug resistance. Oncogene 22, 7512–7523 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Debatin, K. M. & Krammer, P. H. Death receptors in chemotherapy and cancer. Oncogene 23, 2950–2966 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Lowe, S. W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Maier, S., Dahlstroem, C., Haefliger, C., Plum, A. & Piepenbrock, C. Identifying DNA methylation biomarkers of cancer drug response. Am. J. Pharmacogenom. 5, 223–232 (2005).

    Article  CAS  Google Scholar 

  9. Taylor, S. T., Hickman, J. A. & Dive, C. Epigenetic determinants of resistance to etoposide regulation of Bcl-XL and Bax by tumor microenvironmental factors. J. Natl Cancer Inst. 92, 18–23 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Valent, P. et al. Cancer stem cell definitions and terminology: the devil is in the details. Nature Rev. Cancer 12, 767–775 (2012).

    Article  CAS  Google Scholar 

  11. Ambudkar, S. V. et al. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 39, 361–398 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Choi, C. H. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell. Int. 5, 30 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Thomas, H. & Coley, H. M. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting P-glycoprotein. Cancer Control 10, 159–165 (2003).

    Article  PubMed  Google Scholar 

  14. Triller, N., Korosec, P., Kern, I., Kosnik, M. & Debeljak, A. Multidrug resistance in small cell lung cancer: expression of P-glycoprotein, multidrug resistance protein 1 and lung resistance protein in chemo-naive patients and in relapsed disease. Lung Cancer 54, 235–240 (2006).

    Article  PubMed  Google Scholar 

  15. Nooter, K. et al. The prognostic significance of expression of the multidrug resistance-associated protein (MRP) in primary breast cancer. Br. J. Cancer 76, 486–493 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zalcberg, J. et al. MRP1 not MDR1 gene expression is the predominant mechanism of acquired multidrug resistance in two prostate carcinoma cell lines. Prostate Cancer Prostatic Dis. 3, 66–75 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Doyle, L. A. et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl Acad. Sci. USA 95, 15665–15670 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Robey, R. W. et al. Inhibition of ABCG2-mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indolocarbazole structure. Mol. Cancer Ther. 6, 1877–1885 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Shukla, S., Chen, Z. S. & Ambudkar, S. V. Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance. Drug Resist. Updat. 15, 70–80 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shervington, A. & Lu, C. Expression of multidrug resistance genes in normal and cancer stem cells. Cancer Invest. 26, 535–542 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Bhatavdekar, J. M. et al. Overexpression of CD44: a useful independent predictor of prognosis in patients with colorectal carcinomas. Ann. Surg. Oncol. 5, 495–501 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Pusztai, L. et al. Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma. Cancer 104, 682–691 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Ruff, P. et al. A randomized, placebo-controlled, double-blind phase 2 study of docetaxel compared to docetaxel plus zosuquidar (LY335979) in women with metastatic or locally recurrent breast cancer who have received one prior chemotherapy regimen. Cancer Chemother. Pharmacol. 64, 763–768 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Szakacs, G. et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell 6, 129–137 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Meijer, C. et al. Relationship of cellular glutathione to the cytotoxicity and resistance of seven platinum compounds. Cancer Res. 52, 6885–6889 (1992).

    CAS  PubMed  Google Scholar 

  26. Schwartz, P. M., Moir, R. D., Hyde, C. M., Turek, P. J. & Handschumacher, R. E. Role of uridine phosphorylase in the anabolism of 5-fluorouracil. Biochem. Pharmacol. 34, 3585–3589 (1985).

    Article  CAS  PubMed  Google Scholar 

  27. Houghton, J. A. & Houghton, P. J. Elucidation of pathways of 5-fluorouracil metabolism in xenografts of human colorectal adenocarcinoma. Eur. J. Cancer Clin. Oncol. 19, 807–815 (1983).

    Article  CAS  PubMed  Google Scholar 

  28. Malet-Martino, M. & Martino, R. Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1): a review. Oncologist 7, 288–323 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Kosuri, K. V., Wu, X., Wang, L., Villalona-Calero, M. A. & Otterson, G. A. An epigenetic mechanism for capecitabine resistance in mesothelioma. Biochem. Biophys. Res. Commun. 391, 1465–1470 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Belanger, A. S., Tojcic, J., Harvey, M. & Guillemette, C. Regulation of UGT1A1 and HNF1 transcription factor gene expression by DNA methylation in colon cancer cells. BMC Mol. Biol. 11, 9 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Toffoli, G. et al. Genotype-driven phase I study of irinotecan administered in combination with fluorouracil/leucovorin in patients with metastatic colorectal cancer. J. Clin. Oncol. 28, 866–871 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Longley, D. B., Harkin, D. P. & Johnston, P. G. 5-fluorouracil: mechanisms of action and clinical strategies. Nature Rev. Cancer 3, 330–338 (2003).

    Article  CAS  Google Scholar 

  33. Palmberg, C. et al. Androgen receptor gene amplification in a recurrent prostate cancer after monotherapy with the nonsteroidal potent antiandrogen Casodex (bicalutamide) with a subsequent favorable response to maximal androgen blockade. Eur. Urol. 31, 216–219 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Sequist, L. V. et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J. Clin. Oncol. 26, 2442–2449 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Bell, D. W. et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nature Genet. 37, 1315–1316 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005). This paper identifies a secondary EGFR mutation (T790M) that confers resistance to gefitinib.

    CAS  PubMed  Google Scholar 

  37. Pao, W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73 (2005).

    PubMed  PubMed Central  Google Scholar 

  38. Coco, S. et al. Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma. J. Hum. Genet. 57, 682–684 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Shin, S., Kim, J., Yoon, S. O., Kim, Y. R. & Lee, K. A. ALK-positive anaplastic large cell lymphoma with TPM3-ALK translocation. Leuk. Res. 36, e143–e145 (2012).

    Article  PubMed  Google Scholar 

  40. Morris, S. W. et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 267, 316–317 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Chen, Y. et al. Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455, 971–974 (2008).

    CAS  PubMed  Google Scholar 

  42. Shaw, A. T. et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 12, 1004–1012 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Camidge, D. R. et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 13, 1011–1019 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Daley, G. Q., Van Etten, R. A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830 (1990).

    Article  CAS  PubMed  Google Scholar 

  45. Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876–880 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Weisberg, E. et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7, 129–141 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Shah, N. P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399–401 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Golas, J. M. et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 63, 375–381 (2003).

    CAS  PubMed  Google Scholar 

  49. Zhou, T. et al. Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem. Biol. Drug Des. 77, 1–11 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. O'Hare, T. et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16, 401–412 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Giles, F. J. et al. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 109, 500–502 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Ramalingam, S. S. et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 30, 3337–3344 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sequist, L. V. et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 3076–3083.

  54. Lee, H. J. et al. Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov. 3, 168–181 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Bouwman, P. & Jonkers, J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nature Rev. Cancer 12, 587–598 (2012).

    Article  CAS  Google Scholar 

  56. Enoch, T. & Norbury, C. Cellular responses to DNA damage: cell-cycle checkpoints, apoptosis and the roles of p53 and ATM. Trends Biochem. Sci. 20, 426–430 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Fan, S. et al. p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. Cancer Res. 54, 5824–5830 (1994).

    CAS  PubMed  Google Scholar 

  58. Kaelin, W. G. The concept of synthetic lethality in the context of anticancer therapy. Nature Rev. Cancer 5, 689–698 (2005).

    Article  CAS  Google Scholar 

  59. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Edwards, S. L. et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111–1115 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Sakai, W. et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451, 1116–1120 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fink, D., Aebi, S. & Howell, S. B. The role of DNA mismatch repair in drug resistance. Clin. Cancer Res. 4, 1–6 (1998).

    CAS  PubMed  Google Scholar 

  63. Martin, S. A. et al. Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2. EMBO Mol. Med. 1, 323–337 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kirschner, K. & Melton, D. W. Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs. Anticancer Res. 30, 3223–3232 (2010).

    CAS  PubMed  Google Scholar 

  65. Lord, R. V. et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin. Cancer Res. 8, 2286–2291 (2002).

    CAS  PubMed  Google Scholar 

  66. Kwon, H. C. et al. Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer. Ann. Oncol. 18, 504–509 (2007).

    Article  PubMed  Google Scholar 

  67. Usanova, S. et al. Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression. Mol. Cancer 9, 248 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Duesberg, P., Stindl, R. & Hehlmann, R. Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy. Proc. Natl Acad. Sci. USA 97, 14295–14300 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Swanton, C. et al. Chromosomal instability determines taxane response. Proc. Natl Acad. Sci. USA 106, 8671–8676 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Faragher, A. J. & Fry, A. M. Nek2A kinase stimulates centrosome disjunction and is required for formation of bipolar mitotic spindles. Mol. Biol. Cell 14, 2876–2889 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhou, W. 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 23, 48–62 (2013). This study identifies a novel predictor of drug response and poor prognosis in cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Letai, A. G. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nature Rev. Cancer 8, 121–132 (2008).

    Article  CAS  Google Scholar 

  74. Sentman, C. L., Shutter, J. R., Hockenbery, D., Kanagawa, O. & Korsmeyer, S. J. Bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67, 879–888 (1991).

    Article  CAS  PubMed  Google Scholar 

  75. Miyashita, T. & Reed, J. C. bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res. 52, 5407–5411 (1992).

    CAS  PubMed  Google Scholar 

  76. Kitada, S. et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. Blood 91, 3379–3389 (1998).

    CAS  PubMed  Google Scholar 

  77. Nita, M. E. et al. 5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins. Br. J. Cancer 78, 986–992 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wang, G. Q. et al. A role for mitochondrial Bak in apoptotic response to anticancer drugs. J. Biol. Chem. 276, 34307–34317 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Chipuk, J. E., Moldoveanu, T., Llambi, F., Parsons, M. J. & Green, D. R. The BCL-2 family reunion. Mol. Cell 37, 299–310 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ni Chonghaile, T. et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334, 1129–1133 (2011). This paper demonstrates the potential to use BH3 profiling as a means to determine response to chemotherapy.

    Article  CAS  PubMed  Google Scholar 

  81. Costa, D. B. et al. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. 4, 1669–1679 (2007).

    Article  PubMed  Google Scholar 

  82. Kuribara, R. et al. Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors. Mol. Cell. Biol. 24, 6172–6183 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gong, Y. et al. Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med. 4, e294 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Faber, A. C. et al. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov. 1, 352–365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ng, K. P. et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nature Med. 18, 521–528 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. van Delft, M. F. et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10, 389–399 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Oltersdorf, T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Konopleva, M. et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10, 375–388 (2006). This paper identifies MCL1 as a key determinant of resistance to ABT-737.

    Article  CAS  PubMed  Google Scholar 

  89. Lin, X. et al. 'Seed' analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737. Oncogene 26, 3972–3979 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Chen, S., Dai, Y., Harada, H., Dent, P. & Grant, S. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res. 67, 782–791 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Zhong, Q., Gao, W., Du, F. & Wang, X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121, 1085–1095 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Schwickart, M. et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature 463, 103–107 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Shore, G. C. & Viallet, J. Modulating the bcl-2 family of apoptosis suppressors for potential therapeutic benefit in cancer. ASH Education Book. 2005, 226–230 (2005).

    Google Scholar 

  94. Konopleva, M. et al. Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res. 68, 3413–3420 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Friberg, A. et al. Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design. J. Med. Chem. 56, 15–30 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hetschko, H., Voss, V., Seifert, V., Prehn, J. H. & Kogel, D. Upregulation of DR5 by proteasome inhibitors potently sensitizes glioma cells to TRAIL-induced apoptosis. FEBS J. 275, 1925–1936 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Pavet, V., Portal, M. M., Moulin, J. C., Herbrecht, R. & Gronemeyer, H. Towards novel paradigms for cancer therapy. Oncogene 30, 1–20 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Wilson, T. R. et al. c-FLIP: a key regulator of colorectal cancer cell death. Cancer Res. 67, 5754–5762 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Wilson, T. R. et al. Procaspase 8 overexpression in non-small-cell lung cancer promotes apoptosis induced by FLIP silencing. Cell Death Differ. 16, 1352–1361 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Kerr, E. et al. Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death Differ. 19, 1317–1327 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hurwitz, J. L. et al. Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent. Eur. J. Cancer 48, 1096–1107 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Hunter, A. M., LaCasse, E. C. & Korneluk, R. G. The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 12, 1543–1568 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Chen, D. J. & Huerta, S. Smac mimetics as new cancer therapeutics. Anticancer Drugs 20, 646–658 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. White, E. Deconvoluting the context-dependent role for autophagy in cancer. Nature Rev. Cancer 12, 401–410 (2012).

    Article  CAS  Google Scholar 

  105. Amaravadi, R. K. et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 117, 326–336 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Sasaki, K. et al. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells. BMC Cancer 10, 370 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kishida, O. et al. Gefitinib (“Iressa”, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells. Cancer Chemother. Pharmacol. 55, 393–403 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Sumitomo, M., Asano, T., Asakuma, J., Horiguchi, A. & Hayakawa, M. ZD1839 modulates paclitaxel response in renal cancer by blocking paclitaxel-induced activation of the epidermal growth factor receptor-extracellular signal-regulated kinase pathway. Clin. Cancer Res. 10, 794–801 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Van Schaeybroeck, S. et al. Epidermal growth factor receptor activity determines response of colorectal cancer cells to gefitinib alone and in combination with chemotherapy. Clin. Cancer Res. 11, 7480–7489 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Van Schaeybroeck, S. et al. Src and ADAM-17-mediated shedding of transforming growth factor-α is a mechanism of acute resistance to TRAIL. Cancer Res. 68, 8312–8321 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Sunnarborg, S. W. et al. Tumor necrosis factor-α converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. J. Biol. Chem. 277, 12838–12845 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Lee, D. C. et al. TACE/ADAM17 processing of EGFR ligands indicates a role as a physiological convertase. Ann. NY Acad. Sci. 995, 22–38 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Kyula, J. N. et al. Chemotherapy-induced activation of ADAM-17: a novel mechanism of drug resistance in colorectal cancer. Clin. Cancer Res. 16, 3378–3389 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhou, B. B. et al. Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. Cancer Cell 10, 39–50 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wheeler, D. L. et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 27, 3944–3956 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sergina, N. V. et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445, 437–441 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007). A study demonstrating the role of MET amplification in gefitinib resistance in EGFR-dependent lung cancer.

    Article  CAS  PubMed  Google Scholar 

  118. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wagle, N. et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J. Clin. Oncol. 29, 3085–3096 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Johannessen, C. M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968–972 (2010). This paper is a good example of how oncogenic bypass can promote drug resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Villanueva, J. et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18, 683–695 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Mao, M. et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin. Cancer Res. 19, 657–667 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Fuchs, B. C. et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res. 68, 2391–2399 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Yao, Z. et al. TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc. Natl Acad. Sci. USA 107, 15535–15540 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl Med. 3, 75ra26 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Uramoto, H., Shimokawa, H., Hanagiri, T., Kuwano, M. & Ono, M. Expression of selected gene for acquired drug resistance to EGFR-TKI in lung adenocarcinoma. Lung Cancer 73, 361–365 (2011).

    Article  PubMed  Google Scholar 

  128. Byers, L. A. et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin. Cancer Res. 19, 279–290 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhang, Z. et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature Genet. 44, 852–860 (2012).

    Article  CAS  PubMed  Google Scholar 

  130. Huang, S. et al. MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. Cell 151, 937–950 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Bhowmick, N. A., Neilson, E. G. & Moses, H. L. Stromal fibroblasts in cancer initiation and progression. Nature 432, 332–337 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Shiao, S. L., Ganesan, A. P., Rugo, H. S. & Coussens, L. M. Immune microenvironments in solid tumors: new targets for therapy. Genes Dev. 25, 2559–2572 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Caligaris-Cappio, F. et al. 'Role of bone marrow stromal cells in the growth of human multiple myeloma. Blood 77, 2688–2693 (1991).

    CAS  PubMed  Google Scholar 

  134. Bhatia, R., McGlave, P. B., Dewald, G. W., Blazar, B. R. & Verfaillie, C. M. Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages. Blood 85, 3636–3645 (1995).

    CAS  PubMed  Google Scholar 

  135. McMillin, D. W., Negri, J. M. & Mitsiades, C. S. The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nature Rev. Drug Discov. 12, 217–228 (2013).

    Article  CAS  Google Scholar 

  136. Ruoslahti, E. & Pierschbacher, M. D. New perspectives in cell adhesion: RGD and integrins. Science 238, 491–497 (1987).

    Article  CAS  PubMed  Google Scholar 

  137. Hoyt, K. et al. Tissue elasticity properties as biomarkers for prostate cancer. Cancer Biomark 4, 213–225 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Damiano, J. S. Integrins as novel drug targets for overcoming innate drug resistance. Curr. Cancer Drug Targets 2, 37–43 (2002).

    Article  CAS  PubMed  Google Scholar 

  139. Danen, E. H. Integrins: regulators of tissue function and cancer progression. Curr. Pharm. Des. 11, 881–891 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Lesniak, D. et al. β1-integrin circumvents the antiproliferative effects of trastuzumab in human epidermal growth factor receptor-2-positive breast cancer. Cancer Res. 69, 8620–8628 (2009).

    Article  CAS  PubMed  Google Scholar 

  141. Gilbert, L. A. & Hemann, M. T. DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355–366 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Wilson, T. R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012). This paper highlights the widespread incidence of ligand-mediated resistance in response to a variety of targeted agents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Dean, M. ABC transporters, drug resistance, and cancer stem cells. J. Mammary Gland Biol. Neoplasia 14, 3–9 (2009).

    Article  PubMed  Google Scholar 

  145. Allikmets, R., Schriml, L. M., Hutchinson, A., Romano-Spica, V. & Dean, M. A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res. 58, 5337–5339 (1998).

    CAS  PubMed  Google Scholar 

  146. Resetkova, E. et al. Prognostic impact of ALDH1 in breast cancer: a story of stem cells and tumor microenvironment. Breast Cancer Res. Treat. 123, 97–108 (2010).

    Article  PubMed  Google Scholar 

  147. Todaro, M., Francipane, M. G., Medema, J. P. & Stassi, G. Colon cancer stem cells: promise of targeted therapy. Gastroenterology 138, 2151–2162 (2010).

    Article  CAS  PubMed  Google Scholar 

  148. Jiang, X. et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia 21, 926–935 (2007).

    Article  CAS  PubMed  Google Scholar 

  149. Tang, M. et al. Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells. Blood 118, 1622–1631 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Clevers, H. The cancer stem cell: premises, promises and challenges. Nature Med. 17, 313–319 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Johnston, P. G. et al. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res. 55, 1407–1412 (1995).

    CAS  PubMed  Google Scholar 

  152. Brown, R. et al. hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents. Oncogene 15, 45–52 (1997).

    Article  CAS  PubMed  Google Scholar 

  153. Arnold, C. N., Goel, A. & Boland, C. R. Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluorouracil in colorectal cancer cell lines. Int. J. Cancer 106, 66–73 (2003).

    Article  CAS  PubMed  Google Scholar 

  154. Sugimoto, Y., Tsukahara, S., Oh-hara, T., Isoe, T. & Tsuruo, T. Decreased expression of DNA topoisomerase I in camptothecin-resistant tumor cell lines as determined by a monoclonal antibody. Cancer Res. 50, 6925–6930 (1990).

    CAS  PubMed  Google Scholar 

  155. Bugg, B. Y., Danks, M. K., Beck, W. T. & Suttle, D. P. Expression of a mutant DNA topoisomerase II in CCRF-CEM human leukemic cells selected for resistance to teniposide. Proc. Natl Acad. Sci. USA 88, 7654–7658 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Giannakakou, P. et al. Paclitaxel-resistant human ovarian cancer cells have mutant β-tubulins that exhibit impaired paclitaxel-driven polymerization. J. Biol. Chem. 272, 17118–17125 (1997).

    Article  CAS  PubMed  Google Scholar 

  157. Kavallaris, M. et al. Multiple microtubule alterations are associated with Vinca alkaloid resistance in human leukemia cells. Cancer Res. 61, 5803–5809 (2001).

    CAS  PubMed  Google Scholar 

  158. Mahon, F. X. et al. Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp, or Src kinase overexpression. Cancer Res. 68, 9809–9816 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Camgoz, A., Gencer, E. B., Ural, A. U. & Baran, Y. Mechanisms responsible for nilotinib resistance in human chronic myeloid leukemia cells and reversal of resistance. Leuk. Lymphoma 54, 1279–1287 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Nagata, Y. et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6, 117–127 (2004).

    Article  CAS  PubMed  Google Scholar 

  161. Recupero, D. et al. Spontaneous and pronase-induced HER2 truncation increases the trastuzumab binding capacity of breast cancer tissues and cell lines. J. Pathol. 229, 390–399 (2013).

    Article  CAS  PubMed  Google Scholar 

  162. Berns, K. et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12, 395–402 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. Lu, Y., Zi, X., Zhao, Y., Mascarenhas, D. & Pollak, M. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J. Natl Cancer Inst. 93, 1852–1857 (2001).

    Article  CAS  PubMed  Google Scholar 

  164. Li, X. Y. et al. Blockade of DNA methylation enhances the therapeutic effect of gefitinib in non-small cell lung cancer cells. Oncol. Rep. 29, 1975–1982 (2013).

    Article  CAS  PubMed  Google Scholar 

  165. Lievre, A. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66, 3992–3995 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. Montagut, C. et al. Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nature Med. 18, 221–223 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Bergethon, K. et al. ROS1 rearrangements define a unique molecular class of lung cancers. J. Clin. Oncol. 30, 863–870 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Oerlemans, R. et al. Molecular basis of bortezomib resistance: proteasome subunit β5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112, 2489–2499 (2008).

    Article  CAS  PubMed  Google Scholar 

  169. Busacca, S. et al. BAK and NOXA are critical determinants of mitochondrial apoptosis induced by bortezomib in mesothelioma. PLoS ONE 8, e65489 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Jahangiri, A. et al. Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of antiangiogenic therapy resistance. Clin. Cancer Res. 19, 1773–1783 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Hu, Y. L. et al. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res. 72, 1773–1783 (2013).

    Article  CAS  Google Scholar 

  172. Piao, Y. et al. Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype. Neuro Oncol. 14, 1379–1392 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by a grant from Cancer Research UK, C212/A13721.

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Correspondence to Daniel B. Longley.

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Competing interests

P.G.J. is employed by Almac Diagnostics and has an ownership interest in both Almac Diagnostics and Fusion Antibodies. He is a consultant/advisor for, and has received honoraria from, Chugai Pharmaceuticals, Sanofi-Aventis and Pfizer. The other authors declare no competing financial interests.

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Glossary

Antimetabolites

A class of drug that interferes with normal cellular metabolism by disrupting the function of a normal cellular metabolite. Examples that are used as anticancer therapies include 5-fluorouracil, methotrexate and pemetrexed.

Gatekeeper residue

A conserved residue that lies at the opening of the ATP-binding pocket in many kinases. Mutations in these sites are frequently observed as a resistance mechanism to inhibitors of oncogenic kinases.

Mismatch repair

(MMR). A mechanism that corrects base–base mismatches, or insertion and deletion mismatches that are caused by DNA polymerase errors during DNA replication.

Nucleotide-excision repair

(NER). A mechanism of repair for DNA damage caused by crosslinking of DNA bases. It is particularly important for resistance to platinum-based chemotherapeutics.

BH3 profiling

A functional assay that can be used to measure how close a cell is to committing to apoptosis. It involves measuring the mitochondrial response to peptides derived from the BH3 domain of BCL-2 family members.

Mitochondrial priming

A measurable property that determines the proximity of a cell to the apoptotic threshold based on its BH3 profile.

Prodiginines

Bioactive secondary metabolites that are produced by bacteria and that have immunosuppressant, anticancer and antimalarial activities.

Fragment-based design

An NMR-based approach that identifies small organic molecules that bind to adjacent sites in a target molecule with relatively low affinity. Linking of two molecules that bind to adjacent sites then generates high-affinity ligands or inhibitors.

Mediator transcription complex

A large (1.2 MDa) multiprotein complex of up to 30 subunits that regulates transcription from a diverse set of RNA polymerase II-controlled promoters.

Orthogonal therapies

Two therapies are considered orthogonal if they target a cancer in two different ways such that a resistance mechanism for the first therapy is unlikely to suppress the activity of the second therapy and vice versa.

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Holohan, C., Van Schaeybroeck, S., Longley, D. et al. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13, 714–726 (2013). https://doi.org/10.1038/nrc3599

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