Abstract 4706: Evaluating the efficacy of RAS(ON) inhibitor RMC-6236 combined with chemotherapy and other targeted therapies in 3D models involving patients with KRAS-mutated pancreatic cancer

Abstract Background: RAS mutations, particularly KRASG12X, are critical oncogenic drivers in pancreatic cancer, with existing KRASG12C inhibitors unable to target other mutations and often leading to resistance. RMC-6236, a multi-selective RAS(ON) inhibitor, demonstrates potent activity in KRASG12X models, but resistance mechanisms that increase mutant RAS(ON) may reduce its effectiveness. The fibrotic tumor microenvironment in pancreatic cancer exacerbates therapy resistance, and combining RMC-6236 with other therapies could overcome both intrinsic and acquired resistances. This study evaluates RMC-6236 efficacy in patient-derived pancreatic tumors harboring KRAS mutations, and the impact of cancer-associated fibroblasts (CAFs) on its potency as a single agent and in combination with other therapies. We also assess its impact on downstream RAS signaling and apoptosis using pro-apoptotic markers. Methods: Patient-derived tumor cells and fibroblasts were treated with RMC-6236 in 2D and 3D viability assays. Patient-derived organoids (PDOs) were generated by combining tumor and fibroblasts in a 1:1 ratio and allowing them to form in media for 72 hours. Synergy studies explored combinations of RMC-6236 with gemcitabine and abraxane chemotherapies, along with other targeted therapies, including CDK7, WNT, and mTOR pathway inhibitors. Samples were stained for α-SMA via immunofluorescence for CAF detection. Western blot analysis assessed RAS pathway inhibition and apoptotic markers. Results: These results demonstrate the efficacy of RMC-6236 in a pancreatic cancer PDO model when combined with other therapeutic agents. Sensitivity to RMC-6236 was assessed in tumor cells, fibroblasts, and tumor-fibroblast co-cultures, yielding IC50 values ranging from 0.1 to 11 nM, 1 to 3.5 nM, and 0.2 to 5 nM, respectively. These results highlight that the presence of CAFs in KRAS-mutated pancreatic cancer PDOs does not affect sensitivity to RMC-6236 treatment. Notably, synergy studies assessing RMC-6236 in combination with chemotherapy agents (gemcitabine and abraxane), as well as WNT inhibitors (WNTi) and CDK7 inhibitors (CDK7i), revealed a significant reduction in IC50 values, with a more than 100-fold decrease (ranging from 0.0001 nM to 0.001 nM). This substantial enhancement in drug potency underscores the synergistic effects of combining RMC-6236 with these agents, particularly with WNTi. Conclusion: The combination of RMC-6236 with standard chemotherapy and targeted therapies enhances its antitumor activity, suggesting a promising strategy for improving therapeutic outcomes in pancreatic cancer. The observed synergistic interactions, especially with WNTi, warrant further investigation in clinical trials to evaluate the potential of this combination approach in improving treatment responses. Citation Format: Taylor Bargenquast, Cherie Wesley, Janith Don, Guangfa Zhang, Tithi Ghosh Halder, Serina Ng, Alexis Weston, Trason Thode, Erkut Borazanci, Mohan Kaadige, Sara A. Byron, Nicholas Schork, Raffaella Soldi, Sunil Sharma. Evaluating the efficacy of RAS(ON) inhibitor RMC-6236 combined with chemotherapy and other targeted therapies in 3D models involving patients with KRAS-mutated pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4706.