Abstract 4728: The selective Yap/Tead inhibitor TY-1054 re-sensitizes acquired resistance to multiple tyrosine kinase-based targeted therapies

Abstract Introduction: Dysregulation of Hippo/YAP signaling is widespread in human tumors. YAP/TEAD activation is one of the major reasons for resistance in response to targeted therapies. Therefore, the Hippo/YAP signaling pathway is an emergent therapeutic target for inhibiting tumor progression and drug resistance. Small molecules that block auto-palmitoylation of TEADs, such as VT3989 (NCT04665206) and BPI-460372 (NCT05789602), have been successfully to enter the clinical trials. TY-1054 is a potent TEAD inhibitor fully developed by TYK Medicines Inc. Results: TY-1054 had excellent efficacy in the H226 CDX and HNSCC PDX mouse models. TY-9591 is a third-generation EGFR inhibitor developed by TYK Medicines and is currently under pivotal Phase III clinical investigation in China. Our studies showed that TY-9591 had excellent efficacy in the PC9 CDX mouse model, but tumors gradually recurred, as Osimertinib did. Drug-tolerant persister (DTP) and Yap/Tead activation are believed to cause drug resistance to Osimertinib. We found that TY-1054 significantly inhibited the expansion of DTP cells that emerged in PC9 and H-1975 cells after TY-9591 treatment. To investigate whether combined YAP inhibition would result in an extension of responses to EGFR therapy, we treated EGFR-driven NSCLC cell lines with TY-1054 and TY-9591. The results showed that the combination treatment not only offered synergistic effects, but also enhanced apoptosis, compared to single-drug treatment. Furthermore, TY-1054 in combination with TY-9591 significantly delayed tumor regrowth in the PC9 CDX mouse model. The renal safety concerns associated with Yap/Tead inhibitors have attracted significant attention. Since the chemical structures of VT3989 and BPI-460372 have not yet been disclosed, we examined the renal toxicities of TY-1054 with reference compounds VT-105, an analog of VT3989, and TY-2225, which is a Tead inhibitor protected by a polymorph patent of Betta Pharma (WO2023155760A1). In a rat renal toxicity experiment, TY-1054 at a dose of 2.5 mg/kg caused much less albuminuria than VT-105 and TY-2225. To address the differences in renal toxicity between species, we performed a mouse renal toxicity study using TY-1054, VT-105, and TY-2225. In terms of preclinical efficacy and safety, the data suggest that TY-1054 is potentially the best-in-class compound compared to its major competitors. In summary, has a favorable PK profile, good drug exposure, manageable tolerance at high drug exposure levels, and a potentially wide therapeutic window. IND clearances from the US FDA and CN NMPA have received in 2024. This study provides a strong rationale for testing TY-1054 in human clinical trials. The successful execution of the TY-1054 clinical trial will provide a powerful solution for future precision oncology. # contributed equally to this work. * To Whom Correspondence should be addressed. Citation Format: Shengli Dong, Apeng Liang, Zhengfei Guo, Meihua Li, Huan Wang, Shuaibo Han, Hongqiang Li, Jing-Lan Mu, Yakun Qi, Chao Zhou, Yu Yu, Xinlong Yang, Lian Fang, Zhiyong He, Haoyun Li, Chengshan Niu, Mingyu Jiang, Xiugui Chen, Shaoqing Chen, Jun Li, Yusheng Wu. The selective Yap/Tead inhibitor TY-1054 re-sensitizes acquired resistance to multiple tyrosine kinase-based targeted therapies [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 4728.