Abstract LB197: VS-7375, a non-covalent dual ON/OFF KRASG12D inhibitor, displays superior activity to ON-only KRASG12D inhibitors in preclinical models of pancreatic cancer

Abstract The FDA approval of two selective OFF-state KRASG12C inhibitors has stimulated comprehensive development of mechanistically distinct inhibitors of additional KRAS mutations. In particular, approximately 20 selective KRASG12D inhibitors are currently in clinical evaluation. Their mechanisms of action include both ON- and OFF-state inhibitors and both covalent and non-covalent inhibitors. Here we compared the activity of VS-7375 (GFH375), a non-covalent dual ON/OFF KRASG12D inhibitor, with the covalent ON-only KRASG12D inhibitor zoldonrasib (RMC-9805). We found that VS-7375 exhibited greater anti-proliferative potency than RMC-9805 in a panel of KRASG12D-mutant pancreatic ductal adenocarcinoma (PDAC) cell lines. VS-7375 was 40-fold less potent in the KRASG12C cell line MIA PaCa-2, indicating high selectivity for KRASG12D. Furthermore, VS-7375 showed near complete inhibition of phosphorylated ERK (pERK) at concentrations as low as 1 nM by 4 hours, which persisted for up to 48 hours, whereas incomplete suppression of pERK was observed with as high as 30 nM of RMC-9805 by 4 hours. RMC-9805 suppressed pERK by 24 hours but required concentrations 10-30x higher than VS-7375 and rebounded by 48 hours. Similarly, we found that VS-7375 exhibited greater potency than RMC-9805 in suppressing phosphorylated AKT and S6, and MYC expression levels. To further compare the durability of inhibition, we performed washout experiments monitoring signaling inhibition after removal of drug. We found that the non-covalent inhibitor VS-7375 exhibited more prolonged signaling inhibition compared with the covalent inhibitor RMC-9805. pERK reduction persisted for up to 48 hours after washout of VS-7375. In contrast, following washout of RMC-9805, pERK rebound was seen by 8 hours with near complete rebound by 48 hours despite retention of covalently modified KRAS. This durable effect of VS-7375 may be explained by the long residence time of VS-7375 (18-24 hours). To delineate mechanisms of resistance to VS-7375, we cultured cells at 100-fold the GI50 concentration until subpopulations arose with acquired resistance. Initial evaluation of the resistant cells revealed cross-resistance to other mechanistically distinct RAS inhibitors including the tricomplex inhibitors RMC-9805 and RMC-6236 (daraxonrasib), supporting a mechanism where resistant cells had developed RAS-independent growth. Ongoing studies are aimed at extending our comparison of VS-7375 to other ON-only RAS inhibitors (e.g., RMC-6236). In summary, we reveal superior preclinical activity of VS-7375 compared to RMC-9805. These results suggest that targeting both the ON- and OFF-states of mutant KRAS may provide more clinical benefit than covalent modification of the ON-state only. Citation Format: Brandon L. Mouery, Clint A. Stalnecker, Adrienne D. Cox, Silvia Coma, Jonathan A. Pachter, Channing J. Der. VS-7375, a non-covalent dual ON/OFF KRASG12D inhibitor, displays superior activity to ON-only KRASG12D inhibitors in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB197.