Abstract B096: Acquired resistance to KRAS inhibition modulates the pancreatic cancer tumor microenvironment

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with dismal patient outcomes. Acquired resistance to chemotherapeutics is a major barrier to successful pancreatic cancer treatment. MRTX-1133 is a potent, selective KRAS G12D inhibitor that is in early-phase clinical trials. While initially effective, clinical experience with KRAS G12C inhibitors has shown tumors rapidly acquire therapeutic resistance. The tumor microenvironment (TME) plays a pivotal role in resistance development by activating prosurvival pathways, promoting epithelial-mesenchymal transition (EMT) and stemness, and inhibiting apoptosis. In this study, we sought to understand changes in the PDAC TME associated with acquired resistance to KRAS G12D inhibition. Methods: In order to investigate resistance to KRAS G12D inhibition in PDAC, we developed various mouse and human MRTX-1133 resistant (MRTXR) cell models (FC1199, FC1242, FC1245, and SUIT2). Intriguingly, these models also displayed resistance to several pan-RAS(ON) inhibitors. We utilized flow cytometry analysis to investigate the dynamic changes occurring in the TME following resistance to MRTX-1133, and we employed cytokine array and RNA-seq analyses to elucidate the impact of cancer cells on gene and protein expression of TME cells. Results: A comparative analysis between parental PDAC cells and MRTXR tumors revealed significant alterations within the TME. We found a significant decrease (p=0.013, p=0.045, respectively) in the number of inactivated and naïve CD8 T cells (CD8+/CD69+ and CD44-/CD62L+ cells) in MRTXR tumors. We also observed an upregulation of CXCL1, CCL20, and CXCL2 secretion in MRTXR cells compared to parental cells. Conclusions: Pancreatic cancer cells with acquired resistance to KRAS inhibitors modulate their tumor microenvironment uniquely. Ongoing studies aim to identify the critical pathways responsible for these alterations and to develop alternative treatment strategies for KRAS therapy-resistant tumors. Citation Format: Kevin Christian Montecillo Gulay, Jay Patel, Isabella Ng, Tatiana Hurtado de Mendoza, Herve Tiriac, Andrew Lowy. Acquired resistance to KRAS inhibition modulates the pancreatic cancer tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B096.