Modeling response to the KRAS-G12C inhibitor AZD4625 in KRAS^G12C NSCLC patient-derived xenografts reveals insights into primary resistance mechanisms.

ABSTRACT:

Background

KRAS^G12C alterations are present in ~13% of lung adenocarcinomas. AZD4625 is a covalent small molecule inhibitor that selectively binds and inhibits GDP-KRAS^G12C, leading to reduced cell viability and protein signaling responsible for tumor survival in models with this gain-of-function alteration.

Methods

We studied short-term changes in signaling and mechanisms of primary resistance to AZD4625 in twelve KRAS^G12C lung adenocarcinoma patient-derived xenografts (PDX) and six organoids derived from these twelve models.

Results

Sustained tumor regression in four (33%) PDXs was observed while the remaining eight models were intrinsically resistant to AZD4625. Organoid responses to AZD4625 were concordant with their derived PDXs.

SUBMITTER: Rosen JC 

PROVIDER: S-EPMC12765001 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature