Abstract A072: Strategies to improve KRAS G12D inhibitor (MRTX1133) therapy in pancreatic ductal adenocarcinoma
Authors: Gulay Kevin Christian M. , Esparza Edgar , Zhang Xinlian , Mose Evangeline S. , Weitz Jonathan , Pu Minya , Messer Karen , Lowy Andrew M. , Tiriac Herve 
Published: November 2022

Abstract
Background: More than 90% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic KRAS, with KRAS G12D being the predominant mutation. Recently, a novel KRAS G12D inhibitor, MRTX-1133, has been developed, potentially revolutionizing PDAC treatment. However, clinical studies on KRAS G12C inhibitors suggest that there may be intrinsic resistance to KRAS inhibitors (KRASi) and acquired resistance can develop rapidly in patients. Moreover, our preliminary data suggest that acquired resistance mechanisms to chemotherapy can also confer partial resistance to KRASi. We hypothesize that effective killing of tumor cells with KRASi will require a rationally designed combinatorial treatment. Methods: We tested chemotherapy and targeted pathway inhibitors which can inhibit signaling upstream and downstream of KRAS to identify drugs that synergize with MRTX-1133. We treated resected human PDAC and mouse tumors from Kras-G12D; P53-R172H; PDX-Cre (KPC) prepared as organotypic slice cultures to test our identified drug combinations. We orthotopically inoculated KPC PDAC cells and treated mice with vehicle, single-agent drugs (MRTX1133 or Afatinib), or combination therapy. We established MRTX-1133-resistant (MRTXR) models in human SUIT2 cells, human organoids and mouse KPC cell lines to study the mechanisms of KRASi resistance. We performed RNA-seq and Reverse Phase Protein Array in these resistance models to identify pathways differentially activated during resistance development. Results: We found that irreversible ErbB inhibitors, Afatinib and Neratinib, had the greatest synergy with MRTX-1133 in parental and in MRTXR cells. We found that combination therapy with MRTX-1133 and Afatinib decreased the number of proliferating cells compared to the control or single-agent treatment in the human and mouse slice cultures. Combination therapy with MRTX1133 and Afatinib significantly reduced tumor growth in mice compared to the vehicle or single-agent controls. We also found that resistant cells demonstrated increased EGFR and HER2 phosphorylation compared to parental cells and that the MRTX-1133 and Afatinib drug combo synergistically decreased EGFR and HER2 phosphorylation. We identified and mapped the differentially expressed pathways and genes involved in KRASi resistance using RNA-seq and RPPA analyses. Conclusion: We identified a likely pathway of resistance to novel KRAS G12D inhibitors, and we demonstrate that this resistance can be effectively targeted using existing therapeutics targeting the ErbB pathway.
Citation Format: Kevin Christian M. Gulay, Edgar Esparza, Xinlian Zhang, Evangeline S. Mose, Jonathan Weitz, Minya Pu, Karen Messer, Andrew M. Lowy, Herve Tiriac. Strategies to improve KRAS G12D inhibitor (MRTX1133) therapy in pancreatic ductal adenocarcinoma [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 A072.