This project contains all information pertaining to the replication of key experiments from this paper. It includes the detailed protocols, including reagents and author clarifications. We also include any comments from other contributors, researchers from the Science Exchange network, and further information with the original authors that we have learned since the beginning of the project. When experimental studies begin all data collected will also be deposited here, including data analysis and eventually the final written report. <br> **Original citation:** Garnett M.J., Edelman E.J., Heidorn S.J., Greenman C.D., Dastur A., Lau K.W., Greninger P., Thompson I.R., Luo X., Soares J., Liu Q., Iorio F., Surdez D., Chen L., Milano R.J., Bignell G.R., Tam A.T., Davies H., Stevenson J.A., Barthorpe S., Lutz S.R., Kogera F., Lawrence K., McLaren-Douglas A., Mitropoulos X., Mironenko T., Thi H., Richardson L., Zhou W., Jewitt F., Zhang T., O'Brien P., Boisvert J.L., Price S., Hur W., Yang W., Deng X., Butler A., Choi H.G., Chang J.W., Baselga J., Stamenkovic I., Engelman J.A., Sharma S.V., Delattre O., Saez-Rodriguez J., Gray N.S., Settleman J., Futreal P.A., Haber D.A., Stratton M.R., Ramaswamy S., McDermott U., Benes C.H. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012 Mar 28;483(7391):570-5. doi: 10.1038/nature11005. <br> **Original paper 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.