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Background <p>The tyrosine kinase inhibitor (TKI) imatinib targets KIT and PDGFRA, offering significant therapeutic benefits in advanced gastrointestinal stromal tumors (GISTs). However, the high rate of recurrence following treatment discontinuation suggests that drug-tolerant persister cells (DTPs) may contribute to therapy resistance. Elucidating the mechanisms underlying DTP survival is critical for the development of curative strategies. This study aimed to investigate the role of yes-associated protein (YAP) in DTP survival and to evaluate the efficacy of combining imatinib with YAP inhibitors as a potential therapeutic approach.</p> Methods <p>Imatinib-sensitive GIST cell lines were treated with imatinib to generate DTPs. YAP activity was assessed via western blotting, fluorescence immunostaining, and nuclear-cytoplasmic fractionation. Proliferation and apoptosis assays were conducted to evaluate sensitivity to YAP inhibitors, such as verteporfin. Xenograft mouse models were used to assess the efficacy of combination therapy with imatinib and verteporfin.</p> Results <p>DTPs exhibited increased nuclear localization and activity of YAP, which was reversible upon imatinib withdrawal. YAP inhibitors reduced nuclear YAP levels and showed greater efficacy in DTPs than in parental cells. Combination therapy with imatinib and verteporfin significantly suppressed DTP proliferation and induced apoptosis in vitro. In xenograft models, the combination therapy delayed tumor regrowth after treatment cessation compared to imatinib monotherapy.</p> Conclusions <p>YAP activity was elevated in GIST DTPs, and YAP inhibitors effectively suppressed this activity. The combination of imatinib and YAP inhibitors enhanced tumor growth suppression. These findings underscore the pivotal role of YAP in DTP survival and demonstrate the therapeutic potential of combining imatinib with YAP inhibitors.</p>

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Targeting yes-associated protein to overcome imatinib resistance in gastrointestinal stromal tumor drug-tolerant persister cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月8日

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  • Takashi Yokouchi,
  • Tsuyoshi Takahashi,
  • Toshirou Nishida,
  • Koji Tanaka,
  • Yukinori Kurokawa,
  • Kazuyoshi Yamamoto,
  • Takuro Saito,
  • Takaomi Hagi,
  • Kota Momose,
  • Kotaro Yamashita,
  • Tomoki Makino,
  • Kunihiko Kawai,
  • Satoshi Serada,
  • Minoru Fujimoto,
  • Seiichi Hirota,
  • Kiyokazu Nakajima,
  • Tetsuji Naka,
  • Hidetoshi Eguchi,
  • Yuichiro Doki

摘要

Background

The tyrosine kinase inhibitor (TKI) imatinib targets KIT and PDGFRA, offering significant therapeutic benefits in advanced gastrointestinal stromal tumors (GISTs). However, the high rate of recurrence following treatment discontinuation suggests that drug-tolerant persister cells (DTPs) may contribute to therapy resistance. Elucidating the mechanisms underlying DTP survival is critical for the development of curative strategies. This study aimed to investigate the role of yes-associated protein (YAP) in DTP survival and to evaluate the efficacy of combining imatinib with YAP inhibitors as a potential therapeutic approach.

Methods

Imatinib-sensitive GIST cell lines were treated with imatinib to generate DTPs. YAP activity was assessed via western blotting, fluorescence immunostaining, and nuclear-cytoplasmic fractionation. Proliferation and apoptosis assays were conducted to evaluate sensitivity to YAP inhibitors, such as verteporfin. Xenograft mouse models were used to assess the efficacy of combination therapy with imatinib and verteporfin.

Results

DTPs exhibited increased nuclear localization and activity of YAP, which was reversible upon imatinib withdrawal. YAP inhibitors reduced nuclear YAP levels and showed greater efficacy in DTPs than in parental cells. Combination therapy with imatinib and verteporfin significantly suppressed DTP proliferation and induced apoptosis in vitro. In xenograft models, the combination therapy delayed tumor regrowth after treatment cessation compared to imatinib monotherapy.

Conclusions

YAP activity was elevated in GIST DTPs, and YAP inhibitors effectively suppressed this activity. The combination of imatinib and YAP inhibitors enhanced tumor growth suppression. These findings underscore the pivotal role of YAP in DTP survival and demonstrate the therapeutic potential of combining imatinib with YAP inhibitors.