Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumors.

ABSTRACT:

Background

cKIT kinase overexpression and gain-of-function mutations are the critical pathogenesis of gastrointestinal stromal tumors (GISTs). Although the multiple kinase inhibitors such as imatinib, sunitinib, and regorafenib have been approved for GISTs, the acquisition of polyclonal secondary resistance mutations in KIT is still a limitation for GIST treatment. Here we explored the KIT inhibitory activity of axitinib in preclinical models and describe initial characterization of its activity in GIST patient-derived primary cells.

Methods

The activities of axitinib against mutant KIT were evaluated using protein-based assay and a panel of engineered and GIST-derived cell lines. The binding modes of axitinib-KIT/KIT mutants were analyzed. Four primary cells derived from GI

SUBMITTER: Liu F 

PROVIDER: S-EPMC6535728 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature