Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Integrating molecular diagnostics into anticancer drug discovery

Abstract

In the 1990s, the breast cancer drug trastuzumab (Herceptin; Genentech/Roche) — an antibody specific for human epidermal growth factor receptor 2 (HER2; also known as ERBB2) — was approved based on trials in which HER2 expression levels were used to select patients in clinical trials. This provided support for analogous efforts for drugs that target the epidermal growth factor receptor (EGFR). However, the development of these drugs, such as cetuximab (Erbitux; Bristol–Myers Squibb/Lilly) and gefitinib (Iressa; AstraZeneca), has revealed that EGFR expression is an insufficient and unreliable biomarker to select patients for EGFR-targeted therapies in both lung and colon cancer. Indeed, evidence on patient populations that are likely to respond to such therapies, on the basis of specific mutations in proteins of the targeted pathway, has only recently been clinically validated and incorporated into some of the drug labels. This article highlights lessons learned from the development of the first drugs targeting the EGFR family and discusses strategies to decrease the risk of failure in clinical development by more effectively integrating molecular diagnostics into anticancer drug discovery.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Molecular mechanism of EGFR signal-dependence in epithelial cancers.
Figure 2: Prevalence of predictive biomarkers of response to EGFR inhibitors.
Figure 3: Personalized therapy for lung adenocarcinomas.
Figure 4: On-target approach in the clinical development and registration of anticancer signal transduction therapies.

References

  1. Morgillo, F. & Lee, H. Y. Lonafarnib in cancer therapy. Expert Opin. Investig. Drugs 6, 709–719 (2006).

    Article  Google Scholar 

  2. Giaccone, G. et al. Gefitinib in combination with gemcitabin and cisplatin in advanced non-small cell lung cancer: a phase III trial — INTACT1. J. Clin. Oncol. 22, 777 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Herbst, R. S. et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small cell lung cancer: a phase III trial — INTACT2. J. Clin. Oncol. 22, 785–794 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Twombly, R. Failing survival advantage in crucial trial, future of Iressa is in jeopardy. J. Natl Cancer Inst. 97, 249–250 (2005).

    Article  PubMed  Google Scholar 

  5. Kosaka, T. et al. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res. 64, 8919–8923 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Shigematsu, H. et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J. Natl Cancer Inst. 97, 339–346 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Marchetti, A. et al. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J. Clin. Oncol. 23, 857–865 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Bell, D. W. et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J. Clin. Oncol. 31, 8081–8092 (2005).

    Article  CAS  Google Scholar 

  9. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Pao, W. et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA 101, 13306–13311 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tsao, M. S. et al. Erlotinib in lung cancer — molecular and clinical predictors of outcome. N. Engl. J. Med. 353, 133–144 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Cunningham, D. et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351, 337–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Saltz, L. B. et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J. Clin. Oncol. 22, 1201–1208 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Normanno, N. et al. The ErbB receptors and their ligands in cancer: an overview. Curr. Drug Targets 3, 243–257 (2005).

    Article  Google Scholar 

  16. Press, M. F. et al. Sensitivity of HER-2/neu antibodies in archival tissue samples: potential source of error in immunohistochemical studies of oncogene expression. Cancer Res. 54, 2771–2777 (1994).

    CAS  PubMed  Google Scholar 

  17. Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).

    Article  CAS  PubMed  Google Scholar 

  18. Navolanic, P. M., Steelman, L. S. & McCurey, J. A. EGFR family signaling and its association with breast cancer development and resistance to chemotherapy. Int. J. Oncol. 22, 237–252 (2003).

    CAS  PubMed  Google Scholar 

  19. Ross, J. S. et al. Targeted therapy in breast cancer: the HER-2/neu gene and protein. Mol. Cell. Proteomics 4, 379–398 (2004).

    Article  CAS  Google Scholar 

  20. Hayes, D. F. & Thor, A. D. C-erbB-2 in breast cancer: development of a clinically useful marker. Semin. Oncol. 29, 231–145 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Masood, S. & Bui, M. M. Prognostic and predictive value of HER2/neu oncogene in breast cancer. Microsc. Res. Tech. 59, 102–108 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Schnitt, S. J. & Jacobs, T. W. Current status of HER2 testing: caught between a rock and a hard place. Am. J. Clin. Pathol. 116, 806–810 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Vogel, C. L. et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J. Clin. Oncol. 20, 719–726 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Cobleigh, M. A. et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 17, 2639–2648 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Mass, R. D., Press, M. F., Anderson, S., Murphy, M. & Slamon, D. Improved survival benefit from Herceptin (Trastuzumab) in patients selected by fluorescence in situ hybridization (FISH). Proc. ASCO. 20, 22a Abstract 85 (2001).

  27. Ogura, H., Akiyama, F., Kasumi, F., Kazui, T. & Sakamoto, G. Evaluation of HER-2 status in breast carcinoma by fluorescence in situ hybridization and immunohistochemistry. Breast Cancer 10, 234–240 (2003).

    Article  PubMed  Google Scholar 

  28. Wolff, A. C. et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J. Clin. Oncol. 25, 118–145 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Mass, R. D. et al. The concordance between the clinical trials assay (CTA) and fluorescence in situ hybridization (FISH) in the Herceptin pivotal trials. Proc. Am. Soc. Clin. Oncol. 19, 75A (2000).

  30. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. v.2.2008: Breast Cancer (2008).

  31. Fornier, M., Risio, M., Van Poznak, C. & Seidman, A. HER-2 testing and correlation with efficacy in Trastuzumab therapy. Oncology 16, 1340–1358 (2003).

    Google Scholar 

  32. Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279–280 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Geyer, C. E. et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355, 2733–2743 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Scaltriti, M. et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J. Natl Cancer Inst. 99, 628–638 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Kawamoto, T. et al. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc. Natl Acad. Sci. USA 80, 1337–1341 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. El-Rayes, B. F. & LoRusso, P. M. Targeting the epidermal growth factor receptor. Br. J. Cancer 91, 418–424 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mendelsohn, J. & Baselga, J. Epidermal growth factor receptor targeting in cancer. Semin. Oncol. 33, 369–385 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Chung, K. Y., Shia, J., Kemeny, N. E. & Saltz, L. B. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J. Clin. Oncol. 23, 1803–1810 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Moroni, M. et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 6, 279–286 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Shia, J. et al. Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study. Mod. Pathol. 18, 1350–1356 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Andreyev, H. J., Norman, A. R., Cunningham, D., Oates, J. R. & Clarke, P. A. Kirsten ras mutations in patients with colorectal cancer: the multicenter ''RASCAL'' study. J. Natl Cancer Inst. 90, 675–684 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Bokemeyer, C. et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 27, 663–671 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Van Cutsem, E. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Pirker, R. et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 373, 1525–1531 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Hirsch, F. R. et al. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J. Clin. Oncol. 26, 3351–3357 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Khambata-Ford, S. et al. K-Ras mutations (MT) and EGFR-related markers as potential predictors of cetuximab benefit in 1st line advanced NSCLC: results from the BMS099 study. J. Thorac Oncol. 3, S304 (2008).

    Google Scholar 

  48. O'Byrne, K. J. et al. Molecular and clinical predictors of outcome for cetuximab in non-small cell lung cancer (NSCLC): data from the FLEX study. J. Clin. Oncol. 27, 15S Abstract 8007 (2009).

  49. Gibson, T. B., Ranganathan, A. & Grothey, A. Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clin. Colorectal Cancer 1, 29–31 (2006).

    Article  Google Scholar 

  50. Fry, D. W. Mechanism of action of erbB tyrosine kinase inhibitors. Exp. Cell Res. 10, 131–139 (2003).

    Article  CAS  Google Scholar 

  51. Fukuoka, M. et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J. Clin. Oncol. 15, 2237–2246 (2003).

    Article  CAS  Google Scholar 

  52. Kris, M. G. et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 22, 2149–2158 (2003).

    Article  Google Scholar 

  53. Thatcher, N. et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366, 1527–1537 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. US Food and Drug Administration. FDA public health advisory: new labeling and distribution program for gefitinib (Iressa). Washington, DC. 17 June 2005.

  55. Gatzemeier, U. et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J. Clin. Oncol. 25, 1545–1552 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Herbst, R. S. et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J. Clin. Oncol. 23, 5892–5899 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Shepherd, F. A. et al. National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 353, 123–132 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Uramoto, H. & Mitsudomi, T. Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer? Br. J. Cancer 96, 857–863 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tokumo, M. et al. The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin. Cancer Res. 11, 1167–1173 (2005).

    CAS  PubMed  Google Scholar 

  60. Cortes-Funes, H. et al. Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann. Oncol. 16, 1081–1086 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Eberhard, D. A. et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol. 23, 5900–5909 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Sequist, L. V. et al. Epidermal growth factor receptor mutation testing in the care of lung cancer patients. Clin. Cancer Res. 12, 4403–4408 (2006).

    Article  Google Scholar 

  63. Zhu, C. Q. et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada clinical trials group study BR.21. J. Clin. Oncol. 26, 4268–4275 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Pinter, F. et al. Epidermal growth factor receptor (EGFR) high gene copy number and activating mutations in lung adenocarcinomas are not consistently accompanied by positivity for EGFR protein by standard immunohistochemistry. J. Mol. Diagn. 10, 160–168 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Helfrich, B. A. et al. Antitumor activity of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in non-small cell lung cancer cell lines correlates with gene copy number and EGFR mutations but not EGFR protein levels. Clin. Cancer Res. 12, 7117–7125 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Kim, E. S. et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372, 1809–1818 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Douillard, J. Y. et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J. Clin. Oncol. 28 Dec 2009 (doi: 10.1200/JCO.2009.24.3030).

    Article  CAS  PubMed  Google Scholar 

  69. Li, J. et al. CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors. J. Natl Cancer Inst. 98, 1714–1723 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Hidalgo, M. et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies J. Clin. Oncol. 19, 3267–3279 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Varkondi, E. et al. Biochemical assay-based selectivity profiling of clinically relevant kinase inhibitors on mutant forms of EGF receptor. J. Recept. Signal. Transduct. Res. 28, 295–306 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Riely, G. J., Marks, J. & Pao, W. KRAS mutations in non-small cell lung cancer. Proc. Am. Thorac. Soc. 6, 201–205 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Jackman, D. M. et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin. Cancer Res. 15, 5267–5273 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bonomi, P. D., Buckingham, L. & Coon, J. Selecting patients for treatment with epidermal growth factor tyrosine kinase inhibitors. Clin. Cancer Res. 13, 4606–4612 (2007).

    Article  CAS  Google Scholar 

  75. Lim, K. H. et al. Lack of prognostic value of EGFR mutations in primary resected non-small cell lung cancer. Med. Oncol. 24, 388–393 (2007).

    Article  PubMed  Google Scholar 

  76. Kim, Y. T. et al. Molecular changes of epidermal growth factor receptor (EGFR) and KRAS and their impact on the clinical outcomes in surgically resected adenocarcinoma of the lung. Lung Cancer 59, 111–118 (2008).

    Article  PubMed  Google Scholar 

  77. van Krieken, J. H. et al. KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch. 453, 417–431 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Viani, G. A., Afonso, S. L., Stefano, E. J., De Fendi, L. I. & Soares, F. V. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer 7, 153 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Keri, G. et al. Drug discovery in the kinase inhibitory field using the nested chemical library technology. ASSAY Drug Dev. Techn. 3, 543–551 (2005).

    Article  CAS  Google Scholar 

  80. Vulpetti, A. & Bosotti, R. Sequence and structural analysis of kinase ATP pocket residues. Farmaco. 59, 759–765 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Szántai-Kis, C. et al. Prediction oriented QSAR modelling of EGFR inhibition. Curr. Med. Chem. 13, 277–287 (2006).

    Article  PubMed  Google Scholar 

  82. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 16, 1108–1113 (2007).

    Article  CAS  Google Scholar 

  84. Keri, G. et al. Signal transduction therapy with rationally designed kinase inhibitors. Curr. Signal Transd. 1, 67–95 (2006).

    Article  CAS  Google Scholar 

  85. Jain, K. K. Personalised medicine. Curr. Opin. Mol. Ther. 4, 548–558 (2002).

    CAS  PubMed  Google Scholar 

  86. Cappuzzo, F. et al. Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br. J. Cancer 99, 83–89 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ikehara, N. et al. BRAF mutation associated with dysregulation of apoptosis in human colorectal neoplasms. Int. J. Cancer 115, 943–950 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Endoh, H., Yatabe, Y., Kosaka, T., Kuwano, H. & Mitsudomi, T. PTEN and PIK3CA expression is associated with prolonged survival after gefitinib treatment in EGFR-mutated lung cancer patients. J. Thorac. Oncol. 1, 629–634 (2006).

    PubMed  Google Scholar 

  89. Noro, R. et al. PTEN inactivation in lung cancer cells and the effect of its recovery on treatment with epidermal growth factor receptor tyrosine kinase inhibitors. Int. J. Oncol. 31, 1157–1163 (2007).

    CAS  PubMed  Google Scholar 

  90. Frattini, M. et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br. J. Cancer 97, 1139–1145 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Jhawer, M. et al. PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res. 68, 1953–1961 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Mellinghoff, I. K. et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. 353, 2012–2024 (2006).

    Article  Google Scholar 

  93. Berns, K. et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 4, 395–402 (2007).

    Article  CAS  Google Scholar 

  94. Petak, I., Tillman, D. M. & Houghton, J. A. p53 dependence of Fas induction and acute apoptosis in response to 5-fluorouracil-leucovorin in human colon carcinoma cell lines. Clin. Cancer Res. 6, 4432–4441 (2000).

    CAS  PubMed  Google Scholar 

  95. Petak, I. & Houghton, J. A. Shared pathways: death receptors and cytotoxic drugs in cancer therapy. Pathol. Oncol. Res. 7, 95–106 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Rho, J. K. et al. p53 enhances gefitinib-induced growth inhibition and apoptosis by regulation of Fas in non-small cell lung cancer. Cancer Res. 67, 1163–1169 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Cohen, S. J., Cohen, R. B. & Meropol, N. J. Targeting signal transduction pathways in colorectal cancer — more than skin deep. J. Clin. Oncol. 23, 5374–5385 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Wang, S. E. et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10, 25–38 (2006).

    Article  PubMed  CAS  Google Scholar 

  99. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Gandhi, J. et al. Alterations in genes of the EGFR signaling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines. PLoS One 4, 4576 (2009).

    Article  CAS  Google Scholar 

  101. Wakeling, A. E. et al. Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines. Breast Cancer Res. Treat. 38, 67–73 (1996).

    Article  CAS  PubMed  Google Scholar 

  102. Pratilas, C. A. et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res. 68, 9375–9383 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nature Rev. Cancer 9, 689–698 (2005).

    Article  CAS  Google Scholar 

  104. Pao, W. et al. Integration of molecular profiling into the lung cancer clinic. Cancer Res. 15, 5317–5322 (2009).

    Google Scholar 

  105. Saif, M. W. Secondary hepatic resection as a therapeutic goal in advanced colorectal cancer. World J. Gastroenterol. 15, 3855–3864 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Morelli, M. P. et al. Sequence-dependent antiproliferative effects of cytotoxic drugs and epidermal growth factor receptor inhibitors. Ann. Oncol. 4, 61–66 (2005).

    Article  Google Scholar 

  107. Kim, E. S. et al. Phase II randomized study of biomarker-directed treatment for non-small cell lung cancer (NSCLC): the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial program. J. Clin. Oncol. 27, 15S Abstract 8024 (2009).

  108. Ramanathan, R. K. et al. Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A phase II trial. Cancer Invest. 22, 858–865 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Schilder, R. J. Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study. Clin. Cancer Res. 11, 5539–5548 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Xia, W. et al. Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in ErbB2-overexpressing breast cancers. Cancer Res. 67, 1170–1175 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Guffanti, A. et al. A transcriptional sketch of a primary human breast cancer by 454 deep sequencing. BMC Genomics. 10, 163 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Abraham, J., Earl, H. M., Pharoah, P. D. & Caldas, C. Pharmacogenetics of cancer chemotherapy. Biochim. Biophys. Acta 1766, 168–183 (2006).

    CAS  PubMed  Google Scholar 

  113. Jänsch, L. et al. Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry. Mol. Cell Proteomics 6, 537–547 (2007).

    Article  PubMed  CAS  Google Scholar 

  114. Godl, K. et al. Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signalling. Cancer Res. 65, 6919–6926 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Brehmer, D. et al. Cellular targets of gefitinib. Cancer Res. 65, 379–382 (2005).

    CAS  PubMed  Google Scholar 

  116. Daub, H. et al. Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol. Cell 31, 438–448 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Sharm, K. et al. Proteomics strategy for quantitative protein interaction profiling in cell extracts. Nature Methods 6, 741–744 (2009).

    Article  CAS  Google Scholar 

  118. Bantscheff, M., Scholten, A. & Heck, A. J. Revealing promiscuous drug-target interactions by chemical proteomics. Drug Discov. Today 14, 1021–1029 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Bantscheff, M. et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nature Biotechnol. 25, 994–996 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants (KKKII-05/2005, NKFP_07_A2-NANODRUG, TECH_08_A2-STEMKILL, NAP_BIO_06-FLU_DRUG and OTKA-T046665).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to István Peták.

Ethics declarations

Competing interests

István Peták and Richárd Schwab are co-founders of KPS, a company working in the field of molecular diagnostics. György Kéri and László Őrfi are co-founders of Vichem, a drug discovery company focusing on kinase inhibitors. István Peták and László Kopper have occasionally served on the advisory board of and have received honoraria from the Hungarian subsidies of Roche, AstraZeneca, Merck and Amgen.

Supplementary information

Supplementary information S1 (box)

Case study of an EGFR-TKI treated lung cancer patient (PDF 294 kb)

Supplementary information S2 (table)

Major clinical responses to signal transduction therapies are usually associated with the presence of cancer specific genetic changes detected by molecular diagnostic methods. (PDF 205 kb)

Related links

Related links

FURTHER INFORMATION

István Peták's homepage

KRAS information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Peták, I., Schwab, R., Őrfi, L. et al. Integrating molecular diagnostics into anticancer drug discovery. Nat Rev Drug Discov 9, 523–535 (2010). https://doi.org/10.1038/nrd3135

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3135

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing