Abstract C067: Understanding the tumor extrinsic role of oncogenic Kras in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a 5-year survival rate of 10.8%. Most patients present with locally advanced or metastatic disease which is refractory to therapy. Even when surgical resection is possible, relapse is frequent. Thus, there is a need to understand relapse and treatment resistance in pancreatic cancer to develop more effective treatments. Oncogenic KRAS is a driving mutation in PDA. Work in mouse models demonstrated that oncogenic KRAS drives the initiation of pancreatic cancer. Further, our group and others showed that oncogenic KRAS is required for the maintenance of precursor lesions as well as advanced and metastatic disease. We have recently investigated the extrinsic effects of oncogenic KRAS in precursor lesions of pancreatic cancer; we found that oncogenic KRAS drives reprogramming of precursor associated fibroblasts (PAFs or pre-cancer associated fibroblasts; pre-CAFs) to express immunosuppressive cytokines. The extrinsic effects of oncogenic KRAS in advanced disease have so far not been fully elucidated. In brief, we orthotopically transplanted iKRAS cells —derived from a mouse model of inducible and reversible oncogenic KRAS expression— in the pancreas of syngeneic mice. We then administered Doxycycline (DOX) to induce tumor growth. Once tumors had reached the desired size, we split the mice in two cohorts, one that was kept of DOX and one that was taken off DOX. All the animals were sacrificed 3 days later, tumors were dissected and processed for single cell RNA sequencing. We performed bioinformatics analysis on the tumors using the SEURAT pipeline, and mapped cellular composition, changes in gene expression and predicted interactions regulated by oncogenic KRAS. Interestingly, we discovered that several immunosuppressive pathways are alleviated upon KRAS inactivation, and CD8+ T cell infiltration increases. We and others have described resistance to oncogenic KRAS and eventual relapse in the iKRAS mouse model. Further, clinical data from the first KRAS inhibitors tested in clinical trials (G12C mutant-specific inhibitors in lung adenocarcinoma) similarly revealed initial response followed, in most cases, by relapse. We are thus interested in studying the mechanisms of KRAS inhibition resistance and specifically determine whether immunotherapy can be combined with KRAS inactivation to prevent relapse. Citation Format: Monica E. Bonilla. Understanding the tumor extrinsic role of oncogenic Kras in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C067.