Therapeutic KRAS ^G12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers

Abstract

Recently developed KRAS G12C inhibitory drugs are beneficial to lung cancer patients harboring KRAS G12C mutations, but drug resistance frequently develops. Because of the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, these drugs can indirectly affect antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterized how KRAS G12C inhibition reverses immunosuppression driven by oncogenic KRAS in a number of preclinical lung cancer models with varying levels of immunogenicity. Mechanistically, KRAS G12C inhibition up-regulates interferon signaling via Myc inhibition, leading to reduced tumor infiltration by immunosuppressive cells, enhanced infiltration and activation of cytotoxic T cells, and increased antigen presentation. However, the combination of KRAS G12C inhibitors with immune checkpoint blockade only provides synergistic benefit in the most immunogenic tumor model. KRAS G12C inhibition fails to sensitize cold tumors to immunotherapy, with implications for the design of clinical trials combining KRAS G12C inhibitors with anti-PD1 drugs.

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.…”

“…npj Precision Oncology (2023)15 Published in partnership with The Hormel Institute, University of Minnesota 1234567890():,;…”

Drugging KRAS: current perspectives and state-of-art review

“…However, KRAS G12C inhibition did not sensitize non-immunogenic murine models to immunotherapy. This preclinical finding may guide in selecting patients for combinational clinical trials [ 162 ]. Combinations of G12C inhibitors and immune checkpoint inhibitors are being studied in frontline and refractory settings in NSCLC (NCT04613596, NCT04185883, NCT03600883).…”

159 Xerna tumor microenvironment subtypes as a biomarker in lung cancer patients

“…Within this group, the prevalence of targetable oncogenic drivers within the IS phenotype, such as KRAS G12C, may represent the potential for novel ICI combination therapies. 4 These findings further highlight the importance of adding TME analysis to comprehensive biomarker testing in NSCLC…”