Evaluation of KRAS^G12C Inhibitor Responses in Novel Murine KRAS^G12C Lung Cancer Cell Line Models

Abstract

The 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. To 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. The three lines exhibit similar in vitro sensitivities to KRASG12C 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 KRASG12C mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRASG12C inhibitors.

Durable responses to alectinib in murine models of EML4-ALK lung cancer requires adaptive immunity

“…Similarly, in lung cancer, SHP2 inhibitors induce CXCR2 ligands that recruit myeloid derived suppressor cells and limit the response to this therapy 18 . Multiple groups including ours have recently demonstrated the involvement of anti-tumor immunity in the therapeutic response to KRAS G12C inhibitors 10,12,13,15 . We recently reported the involvement of adaptive immunity in the therapeutic response of murine lung cancer cells driven by oncogenic EGFR to the TKI, osimertinib 14 .…”

“…Our recent published studies demonstrate that EGFR-targeted inhibitors induce an interferon (IFN) response program that varies markedly between distinct EGFR mutant lung cancer cell lines and positively associates with the duration of therapeutic response in EGFR-mutant lung cancer patients 7 . In fact, there is a growing literature supporting the role of host immune cells in overall therapeutic response to precision oncology agents and cytotoxic drugs [8][9][10][11][12][13][14][15][16][17][18][19] . However, the mechanisms whereby TKIs induce factors mediating paracrine signaling to the immune microenvironment, and the contribution to the overall therapeutic response are not well understood.…”