Abstract B092: CDK8 and CXCL2 remodel the tumor microenvironment to contribute to KRASG12D small molecule inhibition resistance in pancreatic ductal adenocarcinoma

Abstract

Abstract Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with over 50% of PDAC patients presenting with KRASG12D mutations. The recent development of small molecule inhibitors targeting KRASG12D has enabled effective targeting of mutant KRAS signaling and suppression of tumor growth; however, the contribution of the tumor microenvironment to the therapeutic efficacy of KRASG12D inhibition and mechanisms of resistance to KRASG12D suppression remain to be fully elucidated. Here, we employed spatial transcriptomics and proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRASG12D inhibition with MRTX1133. MRTX1133 treatment was associated with increased antigen presenting cells (APCs), T cells, and putative tumor-restraining fibroblasts within proximity to cancer cells, suggesting that antigen presentation and remodeling of the local microenvironment facilitates an effective response to KRASG12D inhibition. In the context of relapsed MRTX1133 treated tumors, single cell RNA sequencing and validation identified CDK8 as an intrinsic mediator of resistance and CXCL2 as an extrinsic mediator of resistance. Together, these studies identify APCs and CDK8 as therapeutic targets for enabling long term responses to small molecule KRASG12D inhibition with MRTX1133. Citation Format: Kathleen M. McAndrews, Krishnan K. Mahadevan, Bingrui Li, Amari M. Sockwell, Sami J. Morse, Patience J. Kelly, Michelle L. Kirtley, Meagan R. Conner, Sarah I. Patel, Shreyasee V. Khumbar, Kent A. Arian, Yasaman Barekatain, Barbara A. Moreno Diaz, Hengyu Lyu, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Navid Sobhani, Francesca Paradiso, Vincent Bernard, Paola Guerrero, Haoqiang Ying, Anirban Maitra, Timothy P. Heffernan, Raghu Kalluri. CDK8 and CXCL2 remodel the tumor microenvironment to contribute to KRASG12D small molecule inhibition resistance in pancreatic ductal adenocarcinoma [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 B092.