Abstract LB282: Overcoming chemotherapy resistance in pancreatic cancer: The impact of novel RAS inhibitors and tumor microenvironment modulation

Abstract Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal malignancies, with surgery as the only potentially curative treatment option. However, 85% of patients are inoperable at diagnosis. Chemotherapy, the standard of care for these patients, ultimately fails as virtually all patients develop resistance and progress. Clinical trials exploring panRas and Kras mutant inhibitors in chemotherapy-refractory patients are underway; however, early experience suggests resistance will emerge in most patients. We hypothesize that resistance to chemotherapy and Ras inhibitors will be accompanied by changes in the tumor microenvironment (TME) and that understanding such changes will be key to developing effective, novel therapeutic combinations. To understand resistance mechanisms to chemotherapy in PDAC, we developed chemoresistant (CR) PDAC models. We orthotopically implanted Parental (PT) and CR cells in syngeneic mice and treated these groups with vehicle or MRTX1133. We characterized TME using flow cytometry, single-cell RNA-sequencing (scRNA-seq), multiplex-immunohistochemistry, and immunofluorescence. We employed RNA-seq and cytokine analysis to understand the mechanism of chemoresistant cancer and TME crosstalk. Lastly, we depleted macrophages and/or T cells in vivo to understand how they contribute to KRAS inhibition effect and resistance development. RNA-seq analysis of the CR models shows significant upregulation of the KRAS pathway. CR tumors treated with MRTX1133 had significantly decreased tumor volumes and weights compared to vehicle control and PT tumors. Histological and scRNA-seq analyses showed that, in CR tumors, the epithelial cells and fibroblast compartments comprised a significantly larger fraction, while T cells and macrophage compartments significantly decreased. Specifically, CR tumors have a significantly lower number of macrophages and CD4+ and CD8+ T cells (p<0.001), which MRTX1133 treatment rescued (p<0.001). Moreover, RNA-seq and cytokine arrays revealed that CXCL10 and CCL2 were increased, and GM-CSF and LIF were decreased upon treatment with MRTX1133. Our study demonstrates that KRAS inhibition is very effective in chemorefractory PDAC. Cancer-intrinsic resistance mechanisms to chemotherapy and RAS inhibition lead to an immunosuppressive TME and an expansion of cancer cells. Notably, MRTX1133 treatment in chemoresistant models increases immune cell infiltration, associated with tumor growth control. We observed changes in cytokine expression, with GM-CSF and LIF decreased while CXCL10 and CCL2 increased, suggesting a complex interplay between immune activation and macrophage recruitment. Our findings indicate that the TME partially drives the effectiveness and the development of resistance to RAS inhibitors. Citation Format: Kevin C. Gulay, Jay Patel, Rithika Medari, Alexei Martsinkovskiy, Timothy Pham, Tatiana Hurtado De Mendoza, Andrew M. Lowy, Hervé Tiriac. Overcoming chemotherapy resistance in pancreatic cancer: The impact of novel RAS inhibitors and tumor microenvironment modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB282.