Abstract A27: Mapping of chemical-genetic interactions in breast cancer reveals a mechanism of resistance to PI3K inhibitors
Markus K. Muellner, Iris Z. Uras, Bianca V. Gapp, Sebastian M. B. Nijman · Cancer Research · 2012
Abstract Linking the molecular aberrations of cancer to drug responses allows directing the choice of treatment and to explore new therapeutic applications. We set out to systematically map drug-gene interactions in breast cancer and established a multiplexed assay to study the cellular fitness of a panel of engineered isogenic cells in response to a collection of drugs. This approach so far revealed several synthetic-lethal interactions and drug-resistance mechanisms, including previously discovered interactions from other model systems. Among the novel interactions 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. Citation Format: Markus K. Muellner, Iris Z. Uras, Bianca Gapp, Sebastian M. Nijman. Mapping of chemical-genetic interactions in breast cancer reveals a mechanism of resistance to PI3K inhibitors [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr A27.