A driving test for oncogenic mutations.

Activating mutations in protein kinases are a frequent cause of cancer, and selecting drugs that act on these oncogenic kinases can lead to effective therapies. Targeted or whole-genome sequencing of tumor samples can readily reveal the presence of mutations, but discerning previously uncharacterized activating "driver" mutations that will respond to drug treatment from much more abundant but inconsequential "passenger" mutations is problematic. Chakroborty et al. apply a screening approach that leverages error-prone PCR and a proliferating cell model to identify such gain-of-function mutants in the epidermal growth factor receptor (EGFR) kinase. The screen is validated by the identification of known cancer-promoting mutations and reveals a previously unappreciated oncogenic EGFR mutation, A702V, demonstrating its power for discovery of driver mutations.