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The potential of exploiting DNA-repair defects for optimizing lung cancer treatment

Abstract

The tumor genome is commonly aberrant as a consequence of mutagenic insult and incomplete DNA repair. DNA repair as a therapeutic target has recently received considerable attention owing to the promise of drugs that target tumor-specific DNA-repair enzymes and potentiate conventional cytotoxic therapy through mechanism-based approaches, such as synthetic lethality. Treatment for non-small-cell lung cancer (NSCLC) consists mainly of platinum-based chemotherapy regimens and improvements are urgently needed. Optimizing treatment according to tumor status for DNA-repair biomarkers, such as ERCC1, BRCA1 or RRM1, could predict response to platinum, taxanes and gemcitabine-based therapies, respectively, and might improve substantially the response of individual patients' tumors. Finally, recent data on germline variation in DNA-repair genes may also be informative. Here, we discuss how a molecular and functional DNA-repair classification of NSCLC may aid clinical decision making and improve patient outcome.

Key Points

  • Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide and displays frequent DNA repair dysfunctionality

  • Targeting DNA repair can be a therapeutic strategy in itself, notably using mechanism-based approaches, such as synthetic lethality, chemosensitazion or radiosensitization

  • Several DNA-repair biomarkers, such as ERCC1, BRCA1, RAP80, RRM1, PARP1, MSH2 or DNA-PK, could be used to customize NSCLC therapy and substantially improve patient outcomes

  • Functional DNA-repair assays should be implemented in addition to biomarker analysis to select patients that could benefit from mechanism-based treatments

  • Besides tumor characteristics, host DNA-repair gene profiles could provide useful information

  • Current challenges include the prospective validation of such biomarkers, the choice of methods to analyze such biomarkers molecularly and functionally, and the implementation of the results in clinical decision making

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Figure 1: Main DNA lesions and corresponding DNA-damage-repair pathways.
Figure 2: DNA repair as a therapeutic target.
Figure 3: DNA-repair biomarkers and therapeutic implication.

References

  1. Jemal, A. et al. Cancer statistics, 2009. CA Cancer J. Clin. 59, 225–249 (2009).

    Article  PubMed  Google Scholar 

  2. Scagliotti, G. et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 1835–1842 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Pao, W. & Girard, N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 12, 175–180 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Mogi, A. & Kuwano, H. TP53 mutations in nonsmall cell lung cancer. J. Biomed. Biotechnol. 2011, 583929 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Makowski, L. & Hayes, D. N. Role of LKB1 in lung cancer development. Br. J. Cancer 99, 683–688 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Varella-Garcia, M. Chromosomal and genomic changes in lung cancer. Cell Adh. Migr. 4, 100–106 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Olaussen, K. A. et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N. Engl. J. Med. 355, 983–991 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Jalal, S., Earley, J. N. & Turchi, J. J. DNA repair: from genome maintenance to biomarker and therapeutic target. Clin. Cancer Res. 17, 6973–6984 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kastan, M. B. & Bartek, J. Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Pfeifer, G. P. et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21, 7435–7451 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Zhang, N., Liu, X., Li, L. & Legerski, R. Double-strand breaks induce homologous recombinational repair of interstrand cross-links via cooperation of MSH2, ERCC1-XPF, REV3, and the Fanconi anemia pathway. DNA repair (Amst.) 6, 1670–1678 (2007).

    Article  CAS  Google Scholar 

  12. Chen, C. C., Kennedy, R. D., Sidi, S., Look, A. T. & D'Andrea, A. CHK1 inhibition as a strategy for targeting Fanconi Anemia (FA) DNA repair pathway deficient tumors. Mol. Cancer 8, 24 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Helleday, T., Petermann, E., Lundin, C., Hodgson, B. & Sharma, R. A. DNA repair pathways as targets for cancer therapy. Nat. Rev. Cancer 8, 193–204 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Olivier, M., Hollstein, M. & Hainaut, P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol. 2, a001008 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Peltomäki, P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J. Clin. Oncol. 21, 1174–1179 (2003).

    Article  PubMed  CAS  Google Scholar 

  16. Birch, J. M. et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20, 4621–4628 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Wikenheiser-Brokamp, K. A. Retinoblastoma regulatory pathway in lung cancer. Curr. Mol. Med. 6, 783–793 (2006).

    CAS  PubMed  Google Scholar 

  18. Lindahl, T. & Wood, R. D. Quality control by DNA repair. Science 286, 1897–1905 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Fagbemi, A. F., Orelli, B. & Schärer, O. D. Regulation of endonuclease activity in human nucleotide excision repair. DNA repair (Amst.) 10, 722–729 (2011).

    Article  CAS  Google Scholar 

  20. Altaha, R., Liang, X., Yu, J. J. & Reed, E. Excision repair cross complementing-group 1: gene expression and platinum resistance. Int. J. Mol. Med. 14, 959–970 (2004).

    CAS  PubMed  Google Scholar 

  21. Simon, G. R., Sharma, S., Cantor, A., Smith, P. & Bepler, G. ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cancer. Chest 127, 978–983 (2005).

    Article  PubMed  Google Scholar 

  22. Olaussen, K. A., Fouret, P. & Kroemer, G. ERCC1-specific immunostaining in non-small-cell lung cancer. N. Engl. J. Med. 357, 1559–1561 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Bepler, G. et al. ERCC1 and RRM1 in the international adjuvant lung trial by automated quantitative in situ analysis. Am. J. Pathol. 178, 69–78 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Chen, S., Zhang, J., Wang, R., Luo, X. & Chen, H. The platinum-based treatments for advanced non-small cell lung cancer, is low/negative ERCC1 expression better than high/positive ERCC1 expression? A meta-analysis. Lung Cancer 70, 63–70 (2010).

    Article  PubMed  Google Scholar 

  25. Cobo, M. et al. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J. Clin. Oncol. 25, 2747–2754 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. 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 

  27. Besse, B. et al. ERCC1 influence on the incidence of brain metastases in patients with non-squamous NSCLC treated with adjuvant cisplatin-based chemotherapy. Ann. Oncol. 22, 575–581 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Zhou, W. et al. Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin. Cancer Res. 10, 4939–4943 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Murphy, C. G. & Moynahan, M. E. BRCA gene structure and function in tumor suppression: a repair-centric perspective. Cancer J. 16, 39–47 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Graeser, M. et al. A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer. Clin. Cancer Res. 16, 6159–6168 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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 

  32. Shaheen, M., Allen, C., Nickoloff, J. A. & Hromas, R. Synthetic lethality: exploiting the addiction of cancer to DNA repair. Blood 117, 6074–6082 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Rehman, F. L., Lord, C. J. & Ashworth, A. Synthetic lethal approaches to breast cancer therapy. Nat. Rev. Clin. Oncol. 7, 718–724 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Turner, N., Tutt, A. & Ashworth, A. Hallmarks of 'BRCAness' in sporadic cancers. Nat. Rev. Cancer 4, 814–819 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Lee, M. N. et al. Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer. Clin. Cancer Res. 13, 832–838 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Marsit, C. J. et al. Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival. Oncogene 23, 1000–1004 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Mendes-Pereira, A. M. et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1, 315–322 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. McCabe, N. et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 66, 8109–8115 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Jin, G. et al. PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers. Lung Cancer 69, 279–283 (2010).

    Article  PubMed  Google Scholar 

  41. Powell, C. et al. Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers. Cancer Treat. Rev. 36, 566–575 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Liu, S. K. et al. A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia. Radiother. Oncol. 88, 258–268 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Albert, J. M. et al. Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin. Cancer Res. 13, 3033–3042 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Donawho, C. K. et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin. Cancer Res. 13, 2728–2737 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Miknyoczki, S. J. et al. Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. Mol. Cancer Ther. 2, 371–382 (2003).

    CAS  PubMed  Google Scholar 

  46. Paul, I. et al. PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer. J. Pathol. 224, 564–574 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Rosell, R. et al. BRCA1: a novel prognostic factor in resected non-small-cell lung cancer. PloS ONE 2, e1129 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Bartolucci, R. et al. XPG mRNA expression levels modulate prognosis in resected non-small-cell lung cancer in conjunction with BRCA1 and ERCC1 expression. Clin. Lung Cancer 10, 47–52 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Quinn, J. E. et al. BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res. 63, 6221–6228 (2003).

    CAS  Google Scholar 

  50. Chabalier, C. et al. BRCA1 downregulation leads to premature inactivation of spindle checkpoint and confers paclitaxel resistance. Cell Cycle 5, 1001–1007 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Stordal, B. & Davey, R. A systematic review of genes involved in the inverse resistance relationship between cisplatin and paclitaxel chemotherapy: role of BRCA1. Curr. Cancer Drug Targets 9, 354–365 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Wang, L. et al. ERCC1 and BRCA1 mRNA expression levels in metastatic malignant effusions is associated with chemosensitivity to cisplatin and/or docetaxel. BMC Cancer 8, 97 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Taron, M. et al. BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer. Hum. Mol. Genet. 13, 2443–2449 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Boukovinas, I. et al. Tumor BRCA1, RRM1 and RRM2 mRNA expression levels and clinical response to first-line gemcitabine plus docetaxel in non-small-cell lung cancer patients. PLoS ONE 3, e3695 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Cobo, M. et al. Spanish customized adjuvant trial (SCAT) based on BRCA1 mRNA levels [abstract]. J. Clin. Oncol. 26 (Suppl. 15), a7533 (2008).

    Article  Google Scholar 

  56. Rosell, R. et al. Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression. PLoS ONE 4, e5133 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Yan, J. et al. The ubiquitin-interacting motif containing protein RAP80 interacts with BRCA1 and functions in DNA damage repair response. Cancer Res. 67, 6647–6656 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jiricny, J. The multifaceted mismatch-repair system. Nat. Rev. Mol. Cell Biol. 7, 335–346 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Kouso, H. et al. Expression of mismatch repair proteins, hMLH1/hMSH2, in non-small cell lung cancer tissues and its clinical significance. J. Surg. Oncol. 98, 377–383 (2008).

    Article  PubMed  Google Scholar 

  60. Cooper, W. A. et al. Prognostic significance of DNA repair proteins MLH1, MSH2 and MGMT expression in non-small-cell lung cancer and precursor lesions. Histopathology 52, 613–622 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hsu, H. S. et al. Promoter hypermethylation is the predominant mechanism in hMLH1 and hMSH2 deregulation and is a poor prognostic factor in nonsmoking lung cancer. Clin. Cancer Res. 11, 5410–5416 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Scartozzi, M. et al. Mismatch repair system (MMR) status correlates with response and survival in non-small cell lung cancer (NSCLC) patients. Lung Cancer 53, 103–109 (2006).

    Article  PubMed  Google Scholar 

  63. Hsu, H. S., Lee, I. H., Hsu, W. H., Kao, W. T. & Wang, Y. C. Polymorphism in the hMSH2 gene (gISV12–16T > C) is a prognostic factor in non-small cell lung cancer. Lung Cancer 58, 123–130 (2007).

    Article  PubMed  Google Scholar 

  64. Kamal, N. S. et al. MutS homologue 2 and the long-term benefit of adjuvant chemotherapy in lung cancer. Clin. Cancer Res. 16, 1206–1215 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Martin, S. A. et al. DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell 17, 235–248 (2009).

    Article  CAS  Google Scholar 

  66. 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 

  67. Kanellis, G. et al. Expression of DNA mismatch repair gene MSH2 in cytological material from lung cancer patients. Diagn. Cytopathol. 34, 463–466 (2006).

    Article  PubMed  Google Scholar 

  68. Wang, Y. C. et al. Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples. J. Clin. Invest. 111, 887–895 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lieber, M. R., Ma, Y., Pannicke, U. & Schwarz, K. Mechanism and regulation of human non-homologous DNA end-joining. Nat. Rev. Mol. Cell Biol. 4, 712–720 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Auckley, D. H. et al. Reduced DNA-dependent protein kinase activity is associated with lung cancer. Carcinogenesis 22, 723–727 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Eriksson, A., Yachnin, J., Lewensohn, R. & Nilsson, A. DNA-dependent protein kinase is inhibited by trifluoperazine. Biochem. Biophys. Res. Commun. 283, 726–731 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Izzard, R. A., Jackson, S. P. & Smith, G. C. Competitive and noncompetitive inhibition of the DNA-dependent protein kinase. Cancer Res. 59, 2581–2586 (1999).

    CAS  PubMed  Google Scholar 

  73. Boulton, S., Kyle, S. & Durkacz, B. W. Mechanisms of enhancement of cytotoxicity in etoposide and ionising radiation-treated cells by the protein kinase inhibitor wortmannin. Eur. J. Cancer 36, 535–541 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Zhao, Y. et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. 66, 5354–5362 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Zheng, Z. et al. DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N. Engl. J. Med. 356, 800–808 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Tooker, P., Yen, W. C., Ng, S. C., Negro-Vilar, A. & Hermann, T. W. Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. Cancer Res. 67, 4425–4433 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Kwon, W. S. et al. Ribonucleotide reductase M1 (RRM1) 2464G>A polymorphism shows an association with gemcitabine chemosensitivity in cancer cell lines. Pharmacogenet. Genomics 16, 429–438 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Davidson, J. D. et al. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res. 64, 3761–3766 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Bergman, A. M. et al. In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant. Cancer Res. 65, 9510–9516 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Bepler, G. et al. Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer. J. Thorac. Oncol. 3, 1112–1118 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Ceppi, P. et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann. Oncol. 17, 1818–1825 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Rosell, R. et al. Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer. Oncogene 22, 3548–3553 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Rosell, R. et al. Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin. Cancer Res. 10, 1318–1325 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Souglakos, J. et al. Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine. Br. J. Cancer 98, 1710–1715 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Rosell, R. et al. Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery. Clin. Cancer Res. 10, 4215s–4219s (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Simon, G. et al. Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. J. Clin. Oncol. 25, 2741–2746 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Chiappori, A. et al. Phase II study of first-line sequential chemotherapy with gemcitabine-carboplatin followed by docetaxel in patients with advanced non-small cell lung cancer. Oncology 68, 382–390 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Ceppi, P., Papotti, M. & Scagliotti, G. New strategies for targeting the therapy of NSCLC: the role of ERCC1 and TS. Adv. Med. Sci. 55, 22–25 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Rothschild, S. I., Gautschi, O., Lara, P. N. Jr, Mack, P. C. & Gandara, D. R. Biomarkers of DNA repair and related pathways: significance in non-small cell lung cancer. Curr. Opin. Oncol. 23, 150–157 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Dzagnidze, A. et al. Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy. J. Neurosci. 27, 9451–9457 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Su, Z. et al. A platform for rapid detection of multiple oncogenic mutations with relevance to targeted therapy in non-small-cell lung cancer. J. Mol. Diagn. 13, 74–84 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Orlow, I. et al. DNA damage and repair capacity in patients with lung cancer: prediction of multiple primary tumors. J. Clin. Oncol. 26, 3560–3566 (2008).

    Article  PubMed  Google Scholar 

  93. Gorlova, O. Y. et al. DNA repair capacity and lung cancer risk in never smokers. Cancer Epidemiol. Biomarkers Prev. 17, 1322–1328 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang, L. E. et al. DNA repair capacity in peripheral lymphocytes predicts survival of patients with non-small-cell lung cancer treated with first-line platinum-based chemotherapy. J. Clin. Oncol. 29, 4121–4128 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Camps, C., Sirera, R., Iranzo, V., Taron, M. & Rosell, R. Gene expression and polymorphisms of DNA repair enzymes: cancer susceptibility and response to chemotherapy. Clin. Lung Cancer 8, 369–375 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Gurubhagavatula, S. et al. XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. J. Clin. Oncol. 22, 2594–2601 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. de las Peñas, R. et al. Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. Ann. Oncol. 17, 668–675 (2006).

    Article  PubMed  Google Scholar 

  98. Matakidou, A. et al. Genetic variation in the DNA repair genes is predictive of outcome in lung cancer. Hum. Mol. Genet. 16, 2333–2340 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Shiraishi, K. et al. Association of DNA repair gene polymorphisms with response to platinum-based doublet chemotherapy in patients with non-small-cell lung cancer. J. Clin. Oncol. 28, 4945–4952 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Lara, P. N. Jr et al. The cyclin-dependent kinase inhibitor UCN-01 plus cisplatin in advanced solid tumors: a California cancer consortium phase I pharmacokinetic and molecular correlative trial. Clin. Cancer Res. 11, 4444–4450 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Perez, R. P. et al. Modulation of cell cycle progression in human tumors: a pharmacokinetic and tumor molecular pharmacodynamic study of cisplatin plus the CHK1 inhibitor UCN-01 (NSC 638850). Clin. Cancer Res. 12, 7079–7085 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Edelman, M. J. et al. Phase I and pharmacokinetic study of 7-hydroxystaurosporine and carboplatin in advanced solid tumors. Clin. Cancer Res. 13, 2667–2674 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Fink, D. et al. The role of DNA mismatch repair in platinum drug resistance. Cancer Res. 56, 4881–4886 (1996).

    CAS  PubMed  Google Scholar 

  104. Shrivastav, M., De Haro, L. P. & Nickoloff, J. A. Regulation of DNA double-strand break repair pathway choice. Cell Res. 18, 134–147 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Cédric Verjat for his contribution to the graphical design of the figures. S. Postel-Vinay's PhD is funded by an ESMO translational research fellowship as well as an Institut National du Cancer fellowship 'Soutien pour la formation à la recherche translationnelle en cancérologie 2011'.

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S. Postel-Vinay researched the data for the article. All authors made a substantial contribution to the discussion of the content, wrote the article and edited it prior to submission.

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Correspondence to Jean-Charles Soria.

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J.-C. Soria declares he is a consultant for AstraZeneca, Merck and Sanofi-Aventis and owner of patent WO 2007/105110. C. Lord and A. Ashworth are owners of patents describing the use of PARP inhibitors and also stand to benefit from the ICR 'Rewards to inventors scheme'. The other authors declare no competing interests.

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Postel-Vinay, S., Vanhecke, E., Olaussen, K. et al. The potential of exploiting DNA-repair defects for optimizing lung cancer treatment. Nat Rev Clin Oncol 9, 144–155 (2012). https://doi.org/10.1038/nrclinonc.2012.3

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