Abstract B029: Immune checkpoint mediated resistance to KRASG12D inhibition

Abstract Non-small cell lung cancer (NSCLC) remains a leading cause of cancer deaths in the U. S. KRAS mutations are among the most common oncogenic drivers, with two distinct mutations (G12C and G12D) being the most prevalent in smokers and non-smokers, respectively. This distinct expression has been linked to therapeutic responses, especially to immune checkpoint inhibitors (ICIs). Importantly, CD274/PD-L1 expression varies in the two subtypes, likely explaining different responses to ICI, which shows little efficacy in KRASG12D-mutant tumors. A deeper understanding of how KRASG12D shapes the tumor microenvironment (TME) and how KRAS inhibition interfaces with ICI therapy is needed to guide more effective treatment strategies. Using a KRASG12D genetically engineered mouse model, we have shown that genetic KRASG12D inhibition modulates immunosuppression and immune checkpoint expression in myeloid cells (Lasse-Opsahl 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr B029.