Abstract B083: Transcription factors enhancing anti-tumor chemokine expression and lymphocyte infiltration in KRAS G12C inhibitor-resistant non-small cell lung cancer

Abstract KRAS-mutant non-small cell lung cancer (NSCLC) represents the most prevalent subtype of lung adenocarcinoma. Although recently approved KRAS G12C inhibitors (G12Ci) have shown promise, they achieve an objective response rate (ORR) of only ∼40%. Preclinical studies suggest that G12Ci may enhance anti-tumor immunity by upregulating interferon-stimulated genes (ISGs), increasing MHC class I and PD-L1/2 expression, and promoting lymphocyte infiltration into the tumor microenvironment. Supporting this, early-phase clinical trials combining adagrasib or olomorasib with pembrolizumab have reported improved efficacy, with ORRs ranging from 63–75% (Garassino et al., Ann. Oncol., 2024; Burns et al., JCO, 2024). Nevertheless, 25–37% of patients still fail to respond to G12Ci plus anti-PD-1 therapy, indicating that additional immunosuppressive mechanisms may limit response. The mechanisms driving resistance to G12Ci or MAPK inhibition (MAPKi) in combination with immune checkpoint blockade (ICB) remain poorly understood. Prior studies have implicated loss of STK11/LKB1 and silencing of STING in intrinsic resistance to ICB (Kitajima et al., Cancer Discov., 2019). However, non-genetic resistance mechanisms—particularly in the context of G12Ci treatment—are less well characterized. For instance, a failure to induce ISGs has been noted in MAPKi-treated non-responders with colorectal cancer (Tian et al., Nat Med, 2021), but the underlying cellular processes are not fully elucidated. In our studies, we observed that G12Ci-resistant tumor populations—either within a single cell line or across different models—exhibit increased innate immune signaling via upregulation of ISGs. Interestingly, only a subset of these models also shows increased expression of the C-X-C motif chemokines CXCL9, CXCL10, and CXCL11. In CXCL-secreting models, co-culture with peripheral blood mononuclear cells (PBMCs) results in robust lymphocyte infiltration into 3D tumor spheroids, indicating that CXCL chemokines may play a key role in immune cell recruitment. ATAC-seq analysis of G12Ci-treated CXCL-high lines revealed both activating (IRF1, ZNF384, FOXP1) and repressing (MAF, MAFA) transcription factors (TFs) that potentially regulate CXCL gene expression. Knockout of activating TFs reduced CXCL induction following G12Ci treatment, supporting their functional relevance. These results suggest that G12Ci may stimulate CXCL chemokine expression either by activating transcription or by relieving repression by specific TFs, which may drive lymphocyte recruitment and help convert "immune cold" tumors into "hot" microenvironments. The transcription factors we identified may represent new therapeutic targets to potentiate anti-tumor chemokine signaling and improve responses to immunotherapy. Citation Format: Chendi Li, Anahita Nimbalkar, Melissa Vieira, Usman Syed, Barbara Karakyriakou, James Heather, Christopher Ott, Aaron Hata. Transcription factors enhancing anti-tumor chemokine expression and lymphocyte infiltration in KRAS G12C inhibitor-resistant non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B083.