Triptolide, a natural compound from Thunder God Vine , and its water-soluble prodrug Minnelide have shown potent antitumor activity, including promising single-agent efficacy in patients with pancreatic cancer. We previously demonstrated that triptolide suppresses super-enhancer activity in pancreatic cancer and stromal cells by inhibiting the XPB subunit of TFIIH, leading to downregulation of c-Myc and transcriptional effectors of mutant KRAS signaling. In this study, we assessed whether triptolide/Minnelide can enhance the antitumor activity of RMC-6236, a pan-KRAS inhibitor in clinical development for KRAS mutant cancers. We first evaluated the synergistic effects of triptolide and RMC-6236 on pancreatic cancer cell growth across multiple KRAS-mutant lines, including HPAC (KRAS G12D ), Capan-1 (KRAS G12V ), Hs766T (KRAS Q61H ), and BxPC3 (KRAS wt ). The combination demonstrated strong synergy across a range of concentrations in HPAC and Capan-1 cells and additive effects in BxPC3 and Hs766T. To validate these findings in vivo , we assessed Minnelide in combination with RMC-6236 using an HPAC xenograft model (3 × 10 6 cells, subcutaneous implantation). Mice received oral Minnelide (0.10 or 0.15 mg/kg, QDx21) with or without a low dose of oral RMC-6236 (15 mg/kg, QDx21; n = 10/group). While Minnelide alone showed modest tumor inhibition, both doses of Minnelide significantly enhanced the antitumor efficacy of low dose RMC-6236 after 21 days (p < 0.01, two-way ANOVA). No weight loss or other toxicities were observed in the single agent or combination groups. Taken together, these results demonstrate that triptolide/Minnelide augments the activity of RMC-6236 in vitro and in vivo , supporting further preclinical and potentially clinical evaluation. (This work was supported by Minneamrita Therapeutics, Purple Pansies, and the Pancreas National Advisory Council)