Modeling response to the KRAS-G12C inhibitor AZD4625 in KRASG12C 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. Acute AZD4625 exposure significantly decreased gene expression of the ERK1/2 negative regulator, DUSP6, in all models while protein MAPK and AKT/mTOR signals were downregulated more frequently in the AZD4625-sensitive than AZD4625-resistant cohorts. Analyzing PDX transcriptomes and proteomes identified mTOR signaling as a putative mechanism of primary resistance to AZD4625.

Conclusions: Our findings confirm AZD4625 as a highly active KRAS^G12C inhibitor. This data also supports the use of PDX models in understanding resistance mechanisms that may be leveraged to develop more active combination therapies.