TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors.

ABSTRACT: On-target resistance to next-generation TRK inhibitors in TRK fusion-positive cancers is largely uncharacterized. In patients with these tumors, we found that TRK xDFG mutations confer resistance to type I next-generation TRK inhibitors designed to maintain potency against several kinase domain mutations. Computational modeling and biochemical assays showed that TRKA^G667 and TRKC^G696 xDFG substitutions reduce drug binding by generating steric hindrance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors. Consistently, type II inhibitors impede the growth and TRK-mediated signaling of xDFG-mutant isogenic and patient-derived models. Collectively, these data demonstrate th

SUBMITTER: Cocco E 

PROVIDER: S-EPMC8012405 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature