The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT.

ABSTRACT: FGFR1 has been implicated in numerous cancer types including squamous cell lung cancer, a subset of non-small cell lung cancer with a dismal 5-year survival rate. Small-molecule inhibitors targeting FGFR1 are currently in clinical trials, with AZD4547 being one of the furthest along; however, the development of drug resistance is a major challenge for targeted therapies. A prevalent mechanism of drug resistance in kinases occurs through mutation of the gatekeeper residue, V561M in FGFR1; however, mechanisms underlying V561M resistance to AZD4547 are not fully understood. Here, the cellular consequences of the V561M gatekeeper mutation were characterized, and it was found that although AZD4547 maintains nanomolar affinity for V561M FGFR1, based on in vitro binding assays, cells expre

SUBMITTER: Ryan MR 

PROVIDER: S-EPMC6647014 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature