Abstract

8529 Background: KRAS G12C inhibitors such as adagrasib and sotorasib have shown clinical promise in targeting KRAS G12C -mutated lung cancers; however, most patients develop primary or secondary resistance. A biomarker of response to KRAS G12C inhibitor is needed for better patient stratification and to understand the resistance mechanism. Methods: We analyzed transcriptional correlates of adagrasib treatment outcome in 68 patients in the KRYSTAL-1 trial, a phase 1/2 clinical trial of adagrasib monotherapy in the second line and beyond treatment for NSCLC. We also treated KRAS-mutated lung cancer mouse models and organoids with a KRAS inhibitor for the long term and characterized the resistant tumors’ transcriptional profile to identify resistance mechanisms. We also performed serial gene expression analysis of Kras G12D mutated lung organoids undergoing squamous transformation to identify transcription factor involved in the resistance process. Results: In patients with lung adenocarcinoma with KRAS G12C and STK11/ LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRAS G12C and Kras G12D lung cancer mouse models and organoids, treated with KRAS inhibitors adagrasib and MRTX1133, respectively, reveal that tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. We identify TP63 to be a transcription factor whose expression correlated with squamous transformation. The analysis of lineage plasticity program, adagrasib resistant tumors, and p63 regulon revealed KRT6A to be a common biomarker whose expression correlated with overall survival in the KRYSTAL-1 cohort. Conclusions: KRAS G12C mutated lung adenocarcinoma patients with a higher expression of squamous cell carcinoma gene expression signature respond poorly to adagrasib treatment. Expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.