Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor.

ABSTRACT: The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resista

SUBMITTER: Bauer S 

PROVIDER: S-EPMC8313277 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature