A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer.

Abstract	Linking the molecular aberrations of cancer to drug responses could guide treatment choice and identify new therapeutic applications. However, there has been no systematic approach for analyzing gene-drug interactions in human cells. Here we establish a multiplexed assay to study the cellular fitness of a panel of engineered isogenic cancer cells in response to a collection of drugs, enabling the systematic analysis of thousands of gene-drug interactions. Applying this approach to breast cancer revealed various synthetic-lethal interactions and drug-resistance mechanisms, some of which were known, thereby validating the method. NOTCH pathway activation, which occurs frequently in breast cancer, unexpectedly conferred resistance to phosphoinositide 3-kinase (PI3K) inhibitors, which are currently undergoing clinical trials in breast cancer patients. NOTCH1 and downstream induction of c-MYC over-rode the dependency of cells on the PI3K-mTOR pathway for proliferation. These data reveal a new mechanism of resistance to PI3K inhibitors with direct clinical implications.
Authors	Markus K Muellner, Iris Z Uras, Bianca V Gapp, Claudia Kerzendorfer, Michal Smida, Hannelore Lechtermann, Nils Craig-Mueller, Jacques Colinge, Gerhard Duernberger, Sebastian M B Nijman
Journal	Nature chemical biology (Nat Chem Biol) Vol. 7 Issue 11 Pg. 787-93 (Sep 25 2011) ISSN: 1552-4469 [Electronic] United States
PMID	21946274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents MYC protein, human Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins c-myc MTOR protein, human TOR Serine-Threonine Kinases
Topics	Antineoplastic Agents (pharmacology) Breast Neoplasms (drug therapy, genetics) Cell Line, Tumor Cell Proliferation Drug Resistance, Neoplasm (genetics) Female Gene Expression Regulation, Neoplastic Humans Mutation Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins c-myc (genetics, metabolism) Signal Transduction TOR Serine-Threonine Kinases (genetics, metabolism)

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