Abstract 6841: Mutation specific mechanisms of resistance to oncogenic KRAS inhibition

Abstract Mechanisms of resistance to inhibitors against mutant KRAS are linked to the remodeling of the tumor microenvironment (TME). Understanding this remodeling process during intervention and tumor recurrence will likely guide the development of future therapeutic treatment paradigms with long-term responses. 56% of never-smokers with non-small cell lung cancer have KRASG12D mutant cancer and respond little to immune checkpoint therapy (ICI) compared to smokers, who often have mutations in KRASG12C. Our analysis of the TME in a unique KrasG12D inducible and reversible mouse model of NSCLC using single cell RNA sequencing data shows KrasG12D-dependent control of the TME, particularly of the expression of PDL1 in a subset of myeloid cells. PDL1 expression was found to be KrasG12D dependent as it was reduced significantly when KrasG12D was turned ON in mouse lungs. Interestingly, when KrasG12D was turned OFF, the expression of PDL1 increased, indicating mechanisms of resistance. Furthermore, the cytokine expression and secretion of IL6, a known regulator of PDL1 expression, increased in lung tissue and lung cancer cells derived from this model upon genetic and chemical (MRTX1133) Kras inhibition. Moreover, the mechanisms of resistance to oncogenic Kras inhibition appear to be mutant specific. Transcriptome and secretome analyses in human and murine KrasG12D or KrasG12C mutant lung cancer cells show distinct cytokine regulation upon KRAS inhibition. Identification of mechanisms of resistance like the induction of PDL1 expression upon KrasG12D inhibition may provide a strong rationale for co-treatment of KRAS inhibitors with ICI for KrasG12D never-smokers with NSCLC. Citation Format: Ivana Barravecchia, Emily Lasse-Opsahl, Sophia Cavanaugh, Lily Rober, Rachael Baliira, Marzia Robotti, Rachael Hinshaw, Jennifer M. Lee, Yaqing Zhang, Marina Pasca di Magliano, Stefanie Galbán. Mutation specific mechanisms of resistance to oncogenic KRAS inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6841.