Systematic identification of genomic markers of drug sensitivity in cancer cells

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers of response to targeted agents. To uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred ca...

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Detalles Bibliográficos
Autores principales: Garnett, Mathew J., Edelman, Elena J., Heidorn, Sonja J., Greenman, Chris D., Dastur, Anahita, Lau, King Wai, Greninger, Patricia, Thompson, I. Richard, Luo, Xi, Soares, Jorge, Liu, Qingsong, Iorio, Francesco, Surdez, Didier, Chen, Li, Milano, Randy J., Bignell, Graham R., Tam, Ah T., Davies, Helen, Stevenson, Jesse A., Barthorpe, Syd, Lutz, Stephen R., Kogera, Fiona, Lawrence, Karl, McLaren-Douglas, Anne, Mitropoulos, Xeni, Mironenko, Tatiana, Thi, Helen, Richardson, Laura, Zhou, Wenjun, Jewitt, Frances, Zhang, Tinghu, O’Brien, Patrick, Boisvert, Jessica L., Price, Stacey, Hur, Wooyoung, Yang, Wanjuan, Deng, Xianming, Butler, Adam, Choi, Hwan Geun, Chang, Jae Won, Baselga, Jose, Stamenkovic, Ivan, Engelman, Jeffrey A., Sharma, Sreenath V., Delattre, Olivier, Saez-Rodriguez, Julio, Gray, Nathanael S., Settleman, Jeffrey, Futreal, P. Andrew, Haber, Daniel A., Stratton, Michael R., Ramaswamy, Sridhar, McDermott, Ultan, Benes, Cyril H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349233/
https://www.ncbi.nlm.nih.gov/pubmed/22460902
http://dx.doi.org/10.1038/nature11005
Descripción
Sumario:Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers of response to targeted agents. 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 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 harboring the EWS-FLI1 gene translocation to 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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