title: 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.affiliation: CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Markus K
authors.initials: MK
authors.lastname: Muellner
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Uras
authors.forename: Bianca V
authors.initials: BV
authors.lastname: Gapp
authors.forename: Claudia
authors.initials: C
authors.lastname: Kerzendorfer
authors.forename: Michal
authors.initials: M
authors.lastname: Smida
authors.forename: Hannelore
authors.initials: H
authors.lastname: Lechtermann
authors.forename: Nils
authors.initials: N
authors.lastname: Craig-Mueller
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.forename: Gerhard
authors.initials: G
authors.lastname: Duernberger
authors.forename: Sebastian M B
authors.initials: SM
authors.lastname: Nijman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C489427:MYC protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases