The selective YAP/TEAD inhibitor TY-1054 enhances the efficacy of KRAS inhibitors or Trop2-ADC in multiple solid tumors

Introduction: KRAS is one of the most common somatic mutations associated with human cancers. YAP/TEAD activation is a major cause of resistance to various targeted therapies. Recently, YAP/TEAD signaling has been identified as a synthetic lethal target that can enhance the efficacy of KRAS G12C inhibitors. TY-1054 is a potent YAP/TEAD inhibitor developed by TYK Medicines Inc. Results: 1. TY-1054 not only enhanced the efficacy of FDA-approved KRAS G12C inhibitors, Adagrasib and Sotorasib, in Non-Small Cell Lung Cancer (NSCLC) H1373 and H2122 cells, but also enhanced the efficacy of Divarasib (GDC-6036) and pan-KRASi Daroxonrasib (RMC-6236) in NSCLC H1972 and H2122 cells. 2. TY-1054 not only enhanced the efficacy of KRAS G12Di RMC-9805 in SU.86.86 (PDAC, KRAS G12D) in vitro and in vivo, but also enhanced the efficacy of pan-KRASi Daraxonrasib in SU.86.86 in vitro and in vivo. 3. TY-1054 enhances cetuximab efficacy in head and neck squamous cell carcinoma (HNSCC) Cal33 cells. 4. TY-1054 enhances the efficacy of Trop2-ADC (SKB264/Sac-TMT) in triple-negative breast cancer (TNBC) (MDA-MB 231 and HCC1806), NSCLC (H1975 and HCC827), and trastuzumab-resistant breast cancer (JIMT-1) cells. In summary, TY-1054 has a potentially wide therapeutic window and is currently being evaluated in patients in China. IND clearance from the US FDA was received in 2024. This study provides a strong rationale for testing the combination therapy of TY-1054 and KRAS inhibitors or Trop2-ADC in human clinical trials. The successful execution of the TY-1054 clinical trial will provide a powerful solution for precision oncology. # Shengli Dong and Zhengfei Guo contributed equally to this work. * Correspondence to: Shengli Dong, Ph.D.; TYK Medicines Inc.; Block D, No. 778 Huaxi Avenue, Changxing, Zhejiang, P. R. China, 313100. Tel: 86 17772745590; e-mail: shengli.dong@tykmedicines.com.