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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.

Original publication




Journal article


Nat Chem Biol

Publication Date





787 - 793


Antineoplastic Agents, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Mutation, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-myc, Signal Transduction, TOR Serine-Threonine Kinases