Abstract The KRAS(G12C) mutation is the most common genetic mutation in North American lung adenocarcinoma patients. Recently, direct inhibitors of the KRAS G12C 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. To provide models for further preclinical improvement of these inhibitors, we generated three novel murine KRAS G12C -driven lung cancer cell lines. The co-occurring NRAS Q61L mutation in KRAS G12C -positive LLC cells was deleted and the KRAS G12V allele in CMT167 cells was edited to KRAS G12C with CRISPR/Cas9 methods. Also, a novel murine KRAS G12C line, mKRC.1, was established from a tumor generated in a genetically-engineered mouse model. The three lines exhibit similar in vitro sensitivities to KRAS G12C inhibitors (MRTX-1257, AMG-510), but distinct in vivo responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to marked shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic in vitro growth inhibition with MRTX-1257 and the SHP2 inhibitor, RMC-4550 and the MRTX-849/RMC-4550 combination yielded tumor shrinkage in orthotopic LLC-NRAS KO tumors propagated in syngeneic mice. Notably, this synergistic combination response was lost in athymic nu/nu mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs. These new models of murine KRAS G12C mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRAS G12C inhibitors. Contribution to the Field Statement The development of KRAS G12C inhibitors has not impacted treatment of lung cancers bearing the KRAS G12C mutation to the degree that tyrosine kinase inhibitors have changed the treatment outcomes for patients bearing oncogenic mutations in receptor tyrosine kinases. Thus, the field is now exploring combination strategies with KRAS G12C inhibitors that may enhance their clinical benefit. Moreover, published findings indicate that host immunity contributes to efficacy of oncogene-directed inhibitors including KRAS G12C inhibitors. Thus, these novel murine KRAS G12C -driven lung cancer cell lines will provide valuable models for preclinical evaluation of novel drug combinations in immune competent hosts.

Evaluation of KRASG12C Inhibitor Responses in Novel Murine KRASG12C Lung Cancer Cell Line Models