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Abstract A27: Mapping of chemical-genetic interactions in breast cancer reveals a mechanism of resistance to PI3K inhibitors
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...
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Published in: | Cancer research (Chicago, Ill.) Ill.), 2012-07, Vol.72 (13_Supplement), p.A27-A27 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | 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. |
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ISSN: | 0008-5472 1538-7445 |
DOI: | 10.1158/1538-7445.CSB12-A27 |