Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110 alpha.

ABSTRACT: p110 alpha (PIK3CA) is the most frequently mutated kinase in human cancer, and numerous drugs targeting this kinase are currently in preclinical development or early-stage clinical trials. Clinical resistance to protein kinase inhibitors frequently results from point mutations that block drug binding; similar mutations in p110 alpha are likely, but currently none have been reported. Using a S. cerevisiae screen against a structurally diverse panel of PI3K inhibitors, we have identified a potential hotspot for resistance mutations (I800), a drug-sensitizing mutation (L814C), and a surprising lack of resistance mutations at the "gatekeeper" residue. Our analysis further reveals that clinical resistance to these drugs may be attenuated by using multitargeted inhibitors that simultaneously inh

SUBMITTER: Zunder ER 

PROVIDER: S-EPMC2720137 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature