Deletion Mutations Keep Kinase Inhibitors in the Loop

Abstract

Effective clinical application of conformationally selective kinase inhibitors requires tailoring drug choice to the tumor's activating mutation(s). In this issue of Cancer Cell, Foster et al. (2016) describe how activating deletions in BRAF, EGFR, and HER2 cause primary resistance to common inhibitors, suggesting strategies for improved inhibitor selection.

Figure 1. Activating Deletion Mutations Change Kinase Inhibitor Selectivity

Cartoon of kinase domain regulation in the EGFR family or RAF. In the wild-type kinase, helix αC is normally held in the “out” position by interactions with a short helix in the activation loop (A-loop). Upon activation, the A-loop is reorganized, freeing αC to adopt the “in” position and contribute to the active site through a salt bridge between a key glutamate (red) in αC and lysine (blue) in strand β3. β3/αC deletions force αC into the “in” position regardless of other influences, promoting A-loop reorganization and kinase activation (lower panel). Whereas the wild-type kinase accommodates inhibitors that bind with αC “in” or “out,” β3/αC-deleted kinase is restricted to inhibitors that will bind when αC is “in.”