Abstract A082: Dual targeting of BET and EP300 with XP-524 in pancreatic cancer lines resistant to KRAS inhibitors

Abstract INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths and is expected to climb to the 2nd most lethal in the USA by 2030. Greater than 90% of all PDAC harbor mutations in the KRAS oncogene resulting in GTPase protein that is constitutively active driving multiple oncogenic programs within cancer cells and within the tumor immune microenvironment. We previously demonstrated that a novel small molecule, XP-524 - a dual epigentic transcriptional inhibitor of BET/EP300, resulted in dramatically reduced expression of KRAS (an ‘eraser’) in preclinical human and murine PDAC models (Principe, et al, Proc Natl Acad Sci U S A. 2022 Jan 25;119(4)). Here, we test the hypothesis that a KRAS-eraser strategy employing XP-524 can overcome resistance mutations to KRAS inhibitors presently in clinical development. METHODS: We treated PDAC cell lines, Panc1 and AsPC1, with KRAS-G12D inhibitor (MRTX1133), selecting surviving cells after each passage. The resulting AsPC1-MR cells displayed a fivefold right-shift in response to MRTX1133; whereas, Panc1-MR cells were insensitive to MRTX1133 treatment. The concentration-response of both parent and resistant cell cultures was assayed after treatment with XP-524, pan-KRAS inhibitor (BI-2865), RAS-ON inhibitor (RMC-6236), or KRAS G12D inhibitor (RMC-9805), measuring antiproliferative potency and both mRNA and protein expression. RESULTS: Panc1-MR cells were resistant to all evaluated KRAS inhibitors in clinical development, showing no response to KRAS inhibitors below 1 µM concentration. Small right shifts in concentration-response were seen for all inhibitors in AsPC1-MR cells. XP-524 retained efficacy as an antiproliferative agent in kinase-resistant PDAC cells, with a small right-shift in antiproliferative potency in Panc1-MR cell cultures relative to parental cell lines. SIGNIFICANCE: The recent development of G12D, pan-KRAS, and RAS-ON inhibitors has extended the potential of RAS-targeted therapies beyond G12C-specific KRAS inhibitors that fail to treat the vast majority of PDAC patients. The rapid development of resistance mutations to kinase inhibitors is well-known and was recapitulated in Panc1-MR cells with acquired resistance to MRTX1133. These PDAC cells were resistant to all RAS kinase inhibitors, including a RAS-ON inhibitor. Transcriptionally erasing of KRAS is a distinct mechanism of action compared to KRAS inhibition. We demonstrate that the KRAS-eraser, XP-524, can overcome resistance to KRAS inhibitors. Kinase inhibitors, whether orthosteric or allosteric in mechanism, often fail patients once resistance mutations are clonally selected. Our work points the way forward to targeting KRAS more comprehensively to extend clinical benefit. Citation Format: Arlinda Lee, Rakesh S. Nair, Gregory RJ. Thatcher, Rui Xiong, Piush Srivastava, VK Gadi, Ajay Rana. Dual targeting of BET and EP300 with XP-524 in pancreatic cancer lines resistant to KRAS inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A082.