Evaluation of KRAS inhibitor responses in novel murine KRAS lung cancer cell line models.

INTRODUCTION

The KRAS(G12C) mutation is the most common genetic mutation in North American lung adenocarcinoma patients. Recently, direct inhibitors of the KRAS protein have been developed and demonstrate clinical response rates of 37-43%. Importantly, these agents fail to generate durable therapeutic responses with median progression-free survival of ~6.5 months.

METHODS

To provide models for further preclinical improvement of these inhibitors, we generated three novel murine KRAS-driven lung cancer cell lines. The co-occurring NRAS mutation in KRAS-positive LLC cells was deleted and the KRAS allele in CMT167 cells was edited to KRAS with CRISPR/Cas9 methods. Also, a novel murine KRAS line, mKRC.1, was established from a tumor generated in a genetically-engineered mouse model.

RESULTS

The three lines exhibit similar sensitivities to KRAS inhibitors (MRTX-1257, MRTX-849, AMG-510), but distinct responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to modest shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic growth inhibition with combinations of MRTX-1257 and the SHP2/PTPN11 inhibitor, RMC-4550. Moreover, treatment with a MRTX-849/RMC-4550 combination yielded transient tumor shrinkage in orthotopic LLC-NRAS KO tumors propagated in syngeneic mice and durable shrinkage of mKRC.1 tumors. Notably, single-agent MRTX-849 activity in mKRC.1 tumors and the combination response in LLC-NRAS KO tumors was lost when the experiments were performed in athymic mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs.

DISCUSSION

These new models of murine KRAS mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRAS inhibitors.