@article{c4a8f2c108784050b0c5f54e37b692f2,
title = "XAn interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules",
abstract = "The high rate of clinical response to protein-kinase-targeting drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer cell line (CCL) profiling to identify additional biomarkers of small-molecule sensitivities. We have quantitatively measured the sensitivity of 242 genomically characterized CCLs to an Informer Set of 354 small molecules that target many nodes in cell circuitry, uncovering protein dependencies that: (1) associate with specific cancer-genomic alterations and (2) can be targeted by small molecules. We have created the Cancer Therapeutics Response Portal (http://www.broadinstitute.org/ctrp) to enable users to correlate genetic features to sensitivity in individual lineages and control for confounding factors of CCL profiling. We report a candidate dependency, associating activating mutations in the oncogene β-catenin with sensitivity to the Bcl-2 family antagonist, navitoclax. The resource can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs matched to patients by their cancer genotype and lineage.",
author = "Amrita Basu and Bodycombe, {Nicole E.} and Cheah, {Jaime H.} and Price, {Edmund V.} and Ke Liu and Schaefer, {Giannina I.} and Ebright, {Richard Y.} and Stewart, {Michelle L.} and Daisuke Ito and Stephanie Wang and Bracha, {Abigail L.} and Ted Liefeld and Mathias Wawer and Gilbert, {Joshua C.} and Wilson, {Andrew J.} and Nicolas Stransky and Kryukov, {Gregory V.} and Vlado Dancik and Jordi Barretina and Garraway, {Levi A.} and Hon, {C. Suk Yee} and Benito Munoz and Bittker, {Joshua A.} and Stockwell, {Brent R.} and Dineo Khabele and Stern, {Andrew M.} and Clemons, {Paul A.} and Shamji, {Alykhan F.} and Schreiber, {Stuart L.}",
note = "Funding Information: This work was supported by the NCI{\textquoteright}s Cancer Target Discovery and Development Network (RC2-CA148399, awarded to S.L.S.). We acknowledge the following colleagues for contributing compounds and for valuable critique: Drs. D. Adams, A. Beeler, J. Bradner, P. Brown, S. Chattopadhyay, C. Chen, A. Choudhury, J. Clardy, E.J. Corey, M. Dai, K. Hartwell, E. Holson, C. Johannessen, A. Koehler, T. Luo, A. G. Myers, J. Paulk, J. Porco, G. Ramachandran, A. Ramanathan, S. Schaus, K.P. Seiler, M.D. Shair, B. Wagner, Q. Wang, and PharmaMar. We thank J. McGrath, G. Wendel, and the Broad Compound Management team for handling the Informer Set; D.-K. Jang, A. Li, and M. Reich for supporting web portal development; and the Biological Samples Platform for providing CCLs. The project was enabled by the Broad Institute Chemical Biology Program and Platform. L.A.G. is a consultant for and equity holder in Foundation Medicine, Inc. and received sponsored research from Novartis. The authors are grateful for the leadership of the CTD 2 Network by Daniela Gerhard (Director, Office of Cancer Genomics, NCI). S.L.S. is an Investigator at the Howard Hughes Medical Institute. ",
year = "2013",
month = aug,
day = "29",
doi = "10.1016/j.cell.2013.08.003",
language = "English",
volume = "154",
pages = "X1151--1161",
journal = "Cell",
issn = "0092-8674",
number = "5",
}