YAP Regulates HER3 Signaling-Driven Adaptive Resistance to RET Inhibitors in RET-Aberrant Cancers.

• Tác giả: Sachiko Arai, Koji Date, Daichi Fujimoto, Yasuhito Fujisaka, Naoki Furuya, Yasuhiro Goto, Soichi Hirai, Mano Horinaka, Masaki Ishida, Yuki Katayama, Hayato Kawachi, Yohei Matsui, Kenji Morimoto, Satoshi Muto, Ryota Nakamura, Kazumi Nishino, Go Saito, Toshiyuki Sakai, Yoshihiko Sakata, Koichi Takayama, Takayuki Takeda, Akihiro Tamiya, Keiko Tanimura, Shinsaku Tokuda, Michiko Tsuchiya, Hisanori Uehara, Satoshi Watanabe, Tadaaki Yamada, Seiji Yano
• Ngôn ngữ: eng
• Ký hiệu phân loại: 133.594 Types or schools of astrology originating in or associated with a
• Thông tin xuất bản: United States : Clinical cancer research : an official journal of the American Association for Cancer Research , 2025
• Bộ sưu tập: NCBI
• ID: 715466

Tóm tắt

PURPOSE: Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKI). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells. EXPERIMENTAL DESIGN: Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate the molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho-receptor tyrosine kinase antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET fusion-positive lung cancer were analyzed for pretreatment YAP expression and correlated with treatment outcomes. RESULTS: In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pretreatment YAP expression in clinical specimens obtained from patients with RET fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes. CONCLUSIONS: The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment. See related commentary by Ortiz-Cuaran and Leonce, p. 958.