Systematic identification of genomic markers of drug sensitivity in cancer cells

  • Nature. 2012 Mar 28;483(7391):570-5. doi: 10.1038/nature11005.
Mathew J Garnett  1 ,  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
Affiliations
  • 1. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
PMID: 22460902 DOI: 10.1038/nature11005
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.