Abstract 7091: DWP216, a TEAD1/2 inhibitor, enhances efficacy of diverse KRAS inhibitors by reversing resistance mechanisms in RAS-dependent cancers

Abstract YAP-TEAD pathway plays critical in regulating cell proliferation, tissue regeneration, and organ size control, and it promotes tumor progression and metastasis in cancer. Additionally, YAP-TEAD pathway not only reinforces anti-apoptotic signaling but also remodels the tumor microenvironment into an immune-evasive state, representing a key mechanism driving drug resistance.DWP216 is a selective TEAD1/2 inhibitor with high selectivity over TEAD3, a TEAD form associated with renal toxicity, conferring a more favorable safety profile than pan-TEAD inhibitors. DWP216 has demonstrated superior efficacy in NF2-deficient tumor models and is currently in the final stages of GLP toxicology studies.KRAS mutations are a major oncogenic target, occurring in approximately 95% of pancreatic cancers and 40% of lung cancers. KRAS mutations also promote YAP-TEAD activation and, when KRAS signaling is inhibited, YAP-TEAD frequently functions as a key adaptive bypass pathway.In this study, we evaluated the combinatorial potential of DWP216 with various KRAS inhibitors. We observed that Hippo pathway gene set is upregulated in KRAS inhibitor-resistant cancer cells. DWP216 demonstrated in vitro combinatorial efficacy not only with a G12C inhibitor but also with a G12D inhibitor and a pan-RAS inhibitor. Resistance-associated mechanisms to KRAS inhibition such as activation of MAPK signaling and the PI3K/mTOR pathway, were observed in KRAS inhibitor-resistant cancer cells. Treatment with DWP216 reduced Hippo pathway activation and restored sensitivity to KRAS inhibition by reversing these compensatory mechanisms. Combination treatment with DWP216 and KRAS inhibitors also increased pro-apoptotic markers. In vivo CDX models harboring KRAS mutations showed strong combinatorial activity of DWP216 with KRAS inhibitor. In conclusion, DWP216 can be effectively combined with various KRAS inhibitors and may be extendable as a combination strategy against RAS-dependent cancers such as PDAC. Citation Format: Bora Yoo, Ye Gi Han, Hye-Been Yoo, Ahreum Kwon, Jiyoon Seok, Youngwoo Choi, Ji-Duck Kim, Hyounmie Doh. DWP216, a TEAD1/2 inhibitor, enhances efficacy of diverse KRAS inhibitors by reversing resistance mechanisms in RAS-dependent cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7091.