Systematic identification of genomic markers of drug sensitivity in cancer cells
Mathew J Garnett, Elena J Edelman, Sonja J Heidorn, Chris D Greenman, Anahita Dastur, King Wai Lau, Patricia Greninger, I Richard Thompson, Xi Luo, Jorge Soares, Qingsong Liu, Francesco Iorio, Didier Surdez, Li Chen, Randy J Milano, Graham R Bignell, Ah T Tam, Helen Davies, Jesse A Stevenson, Syd Barthorpe, Stephen R Lutz, Fiona Kogera, Karl Lawrence, Anne McLaren-Douglas, Xeni Mitropoulos, Tatiana Mironenko, Helen Thi, Laura Richardson, Wenjun Zhou, Frances Jewitt, Tinghu Zhang, Patrick O'Brien, Jessica L Boisvert, Stacey Price, Wooyoung Hur, Wanjuan Yang, Xianming Deng, Adam Butler, Hwan Geun Choi, Jae Won Chang, Jose Baselga, Ivan Stamenkovic, Jeffrey A Engelman, Sreenath V Sharma, Olivier Delattre, Julio Saez-Rodriguez, Nathanael S Gray, Jeffrey Settleman, P Andrew Futreal, Daniel A Haber, Michael R Stratton, Sridhar Ramaswamy, Ultan McDermott, Cyril H Benes, Mathew J Garnett, Elena J Edelman, Sonja J Heidorn, Chris D Greenman, Anahita Dastur, King Wai Lau, Patricia Greninger, I Richard Thompson, Xi Luo, Jorge Soares, Qingsong Liu, Francesco Iorio, Didier Surdez, Li Chen, Randy J Milano, Graham R Bignell, Ah T Tam, Helen Davies, Jesse A Stevenson, Syd Barthorpe, Stephen R Lutz, Fiona Kogera, Karl Lawrence, Anne McLaren-Douglas, Xeni Mitropoulos, Tatiana Mironenko, Helen Thi, Laura Richardson, Wenjun Zhou, Frances Jewitt, Tinghu Zhang, Patrick O'Brien, Jessica L Boisvert, Stacey Price, Wooyoung Hur, Wanjuan Yang, Xianming Deng, Adam Butler, Hwan Geun Choi, Jae Won Chang, Jose Baselga, Ivan Stamenkovic, Jeffrey A Engelman, Sreenath V Sharma, Olivier Delattre, Julio Saez-Rodriguez, Nathanael S Gray, Jeffrey Settleman, P Andrew Futreal, Daniel A Haber, Michael R Stratton, Sridhar Ramaswamy, Ultan McDermott, Cyril H Benes
Abstract
Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.
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References
- Druker BJ, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–2417.
- Kwak EL, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–1703.
- Chapman PB, et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. N Engl J Med. 2011
- McDermott U, Settleman J. Personalized cancer therapy with selective kinase inhibitors: an emerging paradigm in medical oncology. J Clin Oncol. 2009;27:5650–5659.
- Shoemaker RH, et al. Development of human tumor cell line panels for use in disease-oriented drug screening. Prog Clin Biol Res. 1988;276:265–286.
- Weinstein JN, et al. An information-intensive approach to the molecular pharmacology of cancer. Science. 1997;275:343–349.
- McDermott U, et al. Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci U S A. 2007;104:19936–19941.
- Suwaki N, et al. A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma. Sci Transl Med. 2011;3:85ra47. doi:10.1126/scitranslmed.3002004.
- Deng L, et al. Rho-kinase inhibitor, fasudil, suppresses glioblastoma cell line progression in vitro and in vivo. Cancer Biol Ther. 2010;9:875–884.
- Weber DM, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133–2142. doi:10.1056/NEJMoa070596.
- Konecny GE, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66:1630–1639.
- Lynch TJ, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–2139.
- O’Farrell AM, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003;101:3597–3605.
- Kunii K, et al. FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. Cancer Res. 2008;68:2340–2348.
- Byron SA, et al. Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation. Cancer Res. 2008;68:6902–6907. doi:10.1158/0008-5472.CAN-08-0770.
- Vassilev LT, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–848. doi:10.1126/science.1092472.
- Konecny GE, et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clinical cancer research: an official journal of the American Association for Cancer Research. 2011;17:1591–1602. doi:10.1158/1078-0432.CCR-10-2307.
- Boisvert-Adamo K, Longmate W, Abel EV, Aplin AE. Mcl-1 is required for melanoma cell resistance to anoikis. Mol Cancer Res. 2009;7:549–556.
- Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009;9:862–873. doi:10.1038/nrc2763.
- Zou H, Hastie T. Regularization and variable selection via the elastic net. J.R. Statist. Soc. B. 2005;67:301–320.
- Hanafusa H, Torii S, Yasunaga T, Nishida E. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nature cell biology. 2002;4:850–858. doi:10.1038/ncb867.
- Patterson KI, Brummer T, O’Brien PM, Daly RJ. Dual-specificity phosphatases: critical regulators with diverse cellular targets. The Biochemical journal. 2009;418:475–489.
- Dry JR, et al. Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244) Cancer Res. 2010;70:2264–2273. doi:10.1158/0008-5472.CAN-09-1577.
- Guo W, et al. Formation of 17-allylamino-demethoxygeldanamycin (17-AAG) hydroquinone by NAD(P)H:quinone oxidoreductase 1: role of 17-AAG hydroquinone in heat shock protein 90 inhibition. Cancer Res. 2005;65:10006–10015. doi:10.1158/0008-5472.CAN-05-2029.
- Fong PC, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–134.
- McCabe N, et al. BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of Poly (ADP-Ribose) polymerase: an issue of potency. Cancer Biol Ther. 2005;4:934–936.
- Riggi N, et al. Development of Ewing’s sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Res. 2005;65:11459–11468. doi:10.1158/0008-5472.CAN-05-1696.
- Riggi N, et al. Expression of the FUS-CHOP fusion protein in primary mesenchymal progenitor cells gives rise to a model of myxoid liposarcoma. Cancer Res. 2006;66:7016–7023. doi:10.1158/0008-5472.CAN-05-3979.
- Brenner JC, et al. Mechanistic Rationale for Inhibition of Poly(ADP-Ribose) Polymerase in ETS Gene Fusion-Positive Prostate Cancer. Cancer Cell. 2011;19:664–678.
- Balamuth NJ, Womer RB. Ewing’s sarcoma. Lancet Oncol. 2010;11:184–192.
- Jordi Barretina GC, et al. The Cancer Cell Line Encyclopedia: using preclinical models to predict anticancer drug sensitivity. Nature. 2012
- Prieur A, Tirode F, Cohen P, Delattre O. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol Cell Biol. 2004;24:7275–7283. doi:10.1128/MCB.24.16.7275-7283.2004.
- Boland CR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248–5257.
- Greenman CD, et al. PICNIC: an algorithm to predict absolute allelic copy number variation with microarray cancer data. Biostatistics. 2010;11:164–175.
- Bolstad BM, Irizarry RA, Astrand M, Speed TP. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics. 2003;19:185–193.
- Frey BJ, Dueck D. Clustering by passing messages between data points. Science. 2007;315:972–976. doi:10.1126/science.1136800.
- Iorio F, et al. Discovery of drug mode of action and drug repositioning from transcriptional responses. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:14621–14626. doi:10.1073/pnas.1000138107.
- Shannon P, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome research. 2003;13:2498–2504. doi:10.1101/gr.1239303.
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