Abstract The development of allele-specific KRAS inhibitors underscores the importance of understanding the distinct tumor biology associated with common KRAS mutations, G12D and G12C, in genetically engineered mouse models (GEMMs) of non-small cell lung cancer (NSCLC) and patient samples. Lung tumors driven by the most common KRAS mutation, G12C, show delayed onset and slower progression compared to those driven by KRAS G12D in patients and mice. G12C tumors display lower proliferation and increased immune cell engagement, the latter of which is consistent with observations in patient tumors. Allele-specific KRAS G12C/D inhibitors effectively suppress growth of respective autochthonous lung tumors. However, G12D driven tumors relapse more rapidly than G12C driven tumors in autochthonous models, reflecting greater intrinsic aggressiveness. Given this aggressive clinical behavior, we focused on elucidating the mechanism of action and strategies to potentiate KrasG12D inhibition in non-immunogenic and immunogenic lung cancer models. G12D inhibition enhances tumor antigen presentation, activates T cells, and enables antigen-specific cytotoxicity, leading to efficacy with immune checkpoint blockade combination. This combination induces durable immune memory in immunogenic models, but not in non-immunogenic settings. Our findings underscore key differences between KRAS G12D and G12C mutations in shaping lung cancer biology, reveal distinct resistance dynamics under long-term targeted therapy, and uncover immune-mediated mechanisms specific to KRASG12D inhibition with direct clinical and translational relevance. Citation Format: Esra A. Akbay. Kras G12C and G12D driven lung cancers differ in oncogenic potency, immunogenicity, and relapse following Kras inhibition abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr PR012.
Esra A Akbay (Thu,) studied this question.