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

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

doi:https://doi.org/10.1007/s10120-025-01657-z

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

Yokouchi, Takashi; Takahashi, Tsuyoshi; Nishida, Toshirou et al.

Gastric Cancer, 2025

アクセス数:0件（2025-11-09 20:50 集計）

固定URL: https://hdl.handle.net/11094/103010

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タイトル	Targeting yes-associated protein to overcome imatinib resistance in gastrointestinal stromal tumor drug-tolerant persister cells
著者	著者名 Yokouchi, Takashi
	NRID 1000050452389 1000050452389 ORCID 0000-0003-2397-1478 0000-0003-2397-1478 researchmap permalink mihogaoka13611 mihogaoka13611 Scopus Author ID 56182761100 56182761100 著者名 Takahashi, Tsuyoshi
	NRID 1000040263264 1000040263264 著者名 Nishida, Toshirou
	NRID 1000070621019 1000070621019 ORCID 0000-0001-5178-9388 0000-0001-5178-9388 researchmap permalink koji_tanaka koji_tanaka Scopus Author ID 55628548952 55628548952 著者名 Tanaka, Koji
	NRID 1000010470197 1000010470197 researchmap permalink krkw krkw Scopus Author ID 7202562410 7202562410 著者名 Kurokawa, Yukinori
	NRID 1000070528637 1000070528637 researchmap permalink kymamoto13 kymamoto13 Scopus Author ID 12764120500 12764120500 著者名 Yamamoto, Kazuyoshi
	NRID 1000020646468 1000020646468 ORCID 0000-0002-1733-5064 0000-0002-1733-5064 researchmap permalink tsaito19 tsaito19 Scopus Author ID 57211629912 57211629912 著者名 Saito, Takuro
	著者名 Hagi, Takaomi
	NRID 1000050749752 1000050749752 ORCID 0009-0004-2623-2122 0009-0004-2623-2122 researchmap permalink kom2005 kom2005 著者名 Momose, Kota
	NRID 1000020747159 1000020747159 researchmap permalink k-yamashita k-yamashita Scopus Author ID 57191498316 57191498316 著者名 Yamashita, Kotaro
	NRID 1000080528620 1000080528620 researchmap permalink _-_-_- _-_-_- Scopus Author ID 56339970700 56339970700 著者名 Makino, Tomoki
	著者名 Kawai, Kunihiko
	NRID 1000050463302 1000050463302 著者名 Serada, Satoshi
	NRID 1000000379190 1000000379190 著者名 Fujimoto, Minoru
	NRID 1000050218856 1000050218856 著者名 Hirota, Seiichi
	NRID 1000030432537 1000030432537 ORCID 0000-0001-8635-7585 0000-0001-8635-7585 researchmap permalink project_engine project_engine Scopus Author ID 7404396263 7404396263 著者名 Nakajima, Kiyokazu
	NRID 1000030303936 1000030303936 著者名 Naka, Tetsuji
	NRID 1000090542118 1000090542118 ORCID 0000-0002-2318-1129 0000-0002-2318-1129 researchmap permalink abcdabcdabcd abcdabcdabcd Scopus Author ID 7101627772 7101627772 著者名 Eguchi, Hidetoshi
	NRID 1000020291445 1000020291445 researchmap permalink ydoki3251 ydoki3251 Scopus Author ID 7006390687 7006390687 著者名 Doki, Yuichiro
キーワード等	Drug-tolerant persister cells
	GIST
	Yes-associated protein
内容	The version of record of this article, first published in Gastric Cancer (2025), is available online at Publisher’s website: https://doi.org/10.1007/s10120-025-01657-z
抄録	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.
出版者	Springer
収録物名	Gastric Cancer
刊行年月	2025-09-08
言語	英語
ハンドルURL	https://hdl.handle.net/11094/103010
PISSN	14363291
eISSN	14363305
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1007/s10120-025-01657-z
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	text
DCTERMS.bibliographicCitation	Gastric Cancer. 2025
DC.title	Targeting yes-associated protein to overcome imatinib resistance in gastrointestinal stromal tumor drug-tolerant persister cells
DC.creator	Yokouchi, Takashi
	Takahashi, Tsuyoshi
	Nishida, Toshirou
	Tanaka, Koji
	Kurokawa, Yukinori
	Yamamoto, Kazuyoshi
	Saito, Takuro
	Hagi, Takaomi
	Momose, Kota
	Yamashita, Kotaro
	Makino, Tomoki
	Kawai, Kunihiko
	Serada, Satoshi
	Fujimoto, Minoru
	Hirota, Seiichi
	Nakajima, Kiyokazu
	Naka, Tetsuji
	Eguchi, Hidetoshi
	Doki, Yuichiro
DC.publisher	Springer
DC.language' scheme='DCTERMS.RFC1766	英語
DC.type' scheme='DCTERMS.DCMIType	text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-09-08
DC.identifier	https://doi.org/10.1007/s10120-025-01657-z
DC.subject	Drug-tolerant persister cells
	GIST
	Yes-associated protein
DC.description	The version of record of this article, first published in Gastric Cancer (2025), is available online at Publisher’s website: https://doi.org/10.1007/s10120-025-01657-z
DCTERMS.abstract	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.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	103010
citation_title	Targeting yes-associated protein to overcome imatinib resistance in gastrointestinal stromal tumor drug-tolerant persister cells
citation_author	Yokouchi, Takashi
	Takahashi, Tsuyoshi
	Nishida, Toshirou
	Tanaka, Koji
	Kurokawa, Yukinori
	Yamamoto, Kazuyoshi
	Saito, Takuro
	Hagi, Takaomi
	Momose, Kota
	Yamashita, Kotaro
	Makino, Tomoki
	Kawai, Kunihiko
	Serada, Satoshi
	Fujimoto, Minoru
	Hirota, Seiichi
	Nakajima, Kiyokazu
	Naka, Tetsuji
	Eguchi, Hidetoshi
	Doki, Yuichiro
citation_publisher	Springer
citation_language	英語
citation_date	2025-09-08
citation_journal_title	Gastric Cancer
citation_doi	https://doi.org/10.1007/s10120-025-01657-z
citation_public_url	https://hdl.handle.net/11094/103010

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

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