PAK and PI3K pathway activation confers resistance to KRAS^G12C inhibitor sotorasib.

ABSTRACT:

Background

KRAS is a frequently mutated oncogene in human cancer. Clinical studies on the covalent inhibitors of the KRAS^G12C mutant have reported promising results. However, primary and acquired resistance may limit their clinical use.

Methods

Sotorasib-resistant cell lines were established. We explored the signalling pathways activated in these resistant cell lines and their roles in sotorasib resistance.

Results

The resistant cells exhibited increased cell-matrix adhesion with increased levels of stress fibres and focal adherens. p21-activated kinases (PAKs) were activated in resistant cells, which phosphorylate MEK at serine 298 of MEK and serine 338 of c-Raf to activate the mitogen-activated protein kinase pathway. The PAK inhibitors FRAX597 and FRAX48

SUBMITTER: Chan CH 

PROVIDER: S-EPMC9814377 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature