Evaluation of KRASG12C inhibitor responses in novel murine KRASG12C lung cancer cell line models

Abstract

IntroductionThe KRAS(G12C) mutation is the most common genetic mutation in North American lung adenocarcinoma patients. Recently, direct inhibitors of the KRASG12C 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.MethodsTo provide models for further preclinical improvement of these inhibitors, we generated three novel murine KRASG12C-driven lung cancer cell lines. The co-occurring NRASQ61L mutation in KRASG12C-positive LLC cells was deleted and the KRASG12V allele in CMT167 cells was edited to KRASG12C with CRISPR/Cas9 methods. Also, a novel murine KRASG12C line, mKRC.1, was established from a tumor generated in a genetically-engineered mouse model.ResultsThe three lines exhibit similar in vitro sensitivities to KRASG12C inhibitors (MRTX-1257, MRTX-849, AMG-510), but distinct in vivo 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 in vitro 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 nu/nu mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs.DiscussionThese new models of murine KRASG12C mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRASG12C inhibitors.

Combining RASG12C(ON) inhibitor with SHP2 inhibition sensitises immune excluded lung tumours to immune checkpoint blockade: a strategy for turning cold tumours hot

“…Therefore, additional combination therapies that can reshape the TME further may be required to achieve long-term responses using KRAS G12C inhibitors, in particular in patients with immune cold tumours. SHP2 inhibitors not only suppress the adaptive rewiring of signalling within the cancer cells that diminishes sensitivity to KRAS G12C inhibition, but can also directly affect signalling of non-cancer cells within the TME and enhance anti-tumour immune responses 15,[30][31][32][33] . Here, we combine the active state selective RAS G12C (ON) specific compound RMC-4998 with the SHP2 inhibitor RMC-4550 and ICB and investigate the effects of these combinations in preclinical models of lung cancer with varying degrees of immunogenicity.…”