Clinical impact of primary and secondary KIT mutations on the efficacy of molecular-targeted therapies in gastrointestinal stromal tumors

Kawabata, Kota; Takahashi, Tsuyoshi; Nishida, Toshirou; Kurokawa, Yukinori; Yamamoto, Kazuyoshi; Saito, Takuro; Momose, Kota; Yamashita, Kotaro; Tanaka, Koji; Makino, Tomoki; Kawabata, Ryohei; Takeno, Atsushi; Nakajima, Kiyokazu; Hirota, Seiichi; Eguchi, Hidetoshi; Doki, Yuichiro

doi:https://doi.org/10.1007/s10120-025-01639-1

Clinical impact of primary and secondary KIT mutations on the efficacy of molecular-targeted therapies in gastrointestinal stromal tumors

Kawabata, Kota; Takahashi, Tsuyoshi; Nishida, Toshirou et al.

Gastric Cancer, 2025, 28(5), 899-910

Number of Access:58（2025-10-21 22:10 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/102737

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Title	Clinical impact of primary and secondary KIT mutations on the efficacy of molecular-targeted therapies in gastrointestinal stromal tumors
Creator	CreatorName Kawabata, Kota
	NRID 1000050452389 1000050452389 ORCID 0000-0003-2397-1478 0000-0003-2397-1478 researchmap permalink mihogaoka13611 mihogaoka13611 Scopus Author ID 56182761100 56182761100 CreatorName Takahashi, Tsuyoshi
	NRID 1000040263264 1000040263264 CreatorName Nishida, Toshirou
	NRID 1000010470197 1000010470197 researchmap permalink krkw krkw Scopus Author ID 7202562410 7202562410 CreatorName Kurokawa, Yukinori
	NRID 1000070528637 1000070528637 researchmap permalink kymamoto13 kymamoto13 Scopus Author ID 12764120500 12764120500 CreatorName Yamamoto, Kazuyoshi
	NRID 1000020646468 1000020646468 researchmap permalink tsaito19 tsaito19 Scopus Author ID 57211629912 57211629912 CreatorName Saito, Takuro
	NRID 1000050749752 1000050749752 ORCID 0009-0004-2623-2122 0009-0004-2623-2122 researchmap permalink kom2005 kom2005 CreatorName Momose, Kota
	NRID 1000020747159 1000020747159 researchmap permalink k-yamashita k-yamashita Scopus Author ID 57191498316 57191498316 CreatorName Yamashita, Kotaro
	NRID 1000070621019 1000070621019 ORCID 0000-0001-5178-9388 0000-0001-5178-9388 researchmap permalink koji_tanaka koji_tanaka Scopus Author ID 55628548952 55628548952 CreatorName Tanaka, Koji
	NRID 1000080528620 1000080528620 researchmap permalink _-_-_- _-_-_- Scopus Author ID 56339970700 56339970700 CreatorName Makino, Tomoki
	CreatorName Kawabata, Ryohei
	CreatorName Takeno, Atsushi
	NRID 1000030432537 1000030432537 ORCID 0000-0001-8635-7585 0000-0001-8635-7585 researchmap permalink project_engine project_engine Scopus Author ID 7404396263 7404396263 CreatorName Nakajima, Kiyokazu
	NRID 1000050218856 1000050218856 CreatorName Hirota, Seiichi
	NRID 1000090542118 1000090542118 researchmap permalink abcdabcdabcd abcdabcdabcd Scopus Author ID 7101627772 7101627772 ORCID 0000-0002-2318-1129 0000-0002-2318-1129 CreatorName Eguchi, Hidetoshi
	NRID 1000020291445 1000020291445 researchmap permalink ydoki3251 ydoki3251 Scopus Author ID 7006390687 7006390687 CreatorName Doki, Yuichiro
Subject	Gastrointestinal stromal tumors
	Gene mutations
	Genetic profiling
	Molecular-targeted therapy
	Tyrosine kinase inhibitors
Description	The version of record of this article, first published in Gastric Cancer 28 (2025), is available online at Publisher’s website: https://doi.org/10.1007/s10120-025-01639-1.
Abstract	Background: Gastrointestinal stromal tumors (GISTs) are commonly driven by primary mutations in KIT or PDGFRA. Imatinib is the first-line therapy for GISTs. However, secondary mutations frequently emerge during imatinib treatment, contributing to resistance and influencing the efficacy of subsequent tyrosine kinase inhibitors, such as sunitinib and regorafenib. This study aimed to investigate the clinical relevance of both primary and secondary KIT mutations in treating and prognosing unresectable or recurrent GISTs. Methods: Ninety patients with unresectable or recurrent GISTs treated at our institution between 2000 and 2017 were retrospectively analyzed. Genetic testing was performed before the initial drug administration to guide first-line imatinib therapy based on the primary mutation profile. In 64 imatinib-resistant patients, additional genetic testing was conducted on tissues obtained from resistant lesions. Treatment response and prognosis were compared across mutational profiles. Results: The most common primary mutation was KIT exon 11 (76.7%), followed by exon 9 (12.2%). Patients with exon 9 mutations showed superior progression-free survival with sunitinib than those with exon 11 mutations. Among patients with exon 11 primary mutations, secondary mutations were identified in 79.2%, predominantly in KIT exon 13/14 (47.9%) or 17/18 (31.3%). Sunitinib was more effective in patients with secondary exon 13/14 mutations, whereas regorafenib was significantly more effective in those with exon 17/18 mutations. Conclusions: Secondary KIT mutations play a crucial role in imatinib resistance and the efficacy of second- and third-line therapies. Genetic profiling at the initial diagnosis and at the time of resistance may provide more personalized and effective treatment strategies.
Publisher	Springer
Source Title	Gastric Cancer
Volume (Issue)	28(5)
Page	899-910
Date of Issued	2025-07-23
Language	English
Handle URL	https://hdl.handle.net/11094/102737
PISSN	14363291
eISSN	14363305
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1007/s10120-025-01639-1
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Gastric Cancer. 2025, 28(5), p. 899-910
DC.title	Clinical impact of primary and secondary KIT mutations on the efficacy of molecular-targeted therapies in gastrointestinal stromal tumors
DC.creator	Kawabata, Kota
	Takahashi, Tsuyoshi
	Nishida, Toshirou
	Kurokawa, Yukinori
	Yamamoto, Kazuyoshi
	Saito, Takuro
	Momose, Kota
	Yamashita, Kotaro
	Tanaka, Koji
	Makino, Tomoki
	Kawabata, Ryohei
	Takeno, Atsushi
	Nakajima, Kiyokazu
	Hirota, Seiichi
	Eguchi, Hidetoshi
	Doki, Yuichiro
DC.publisher	Springer
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-07-23
DC.identifier	https://doi.org/10.1007/s10120-025-01639-1
DC.subject	Gastrointestinal stromal tumors
	Gene mutations
	Genetic profiling
	Molecular-targeted therapy
	Tyrosine kinase inhibitors
DC.description	The version of record of this article, first published in Gastric Cancer 28 (2025), is available online at Publisher’s website: https://doi.org/10.1007/s10120-025-01639-1.
DCTERMS.abstract	Background: Gastrointestinal stromal tumors (GISTs) are commonly driven by primary mutations in KIT or PDGFRA. Imatinib is the first-line therapy for GISTs. However, secondary mutations frequently emerge during imatinib treatment, contributing to resistance and influencing the efficacy of subsequent tyrosine kinase inhibitors, such as sunitinib and regorafenib. This study aimed to investigate the clinical relevance of both primary and secondary KIT mutations in treating and prognosing unresectable or recurrent GISTs. Methods: Ninety patients with unresectable or recurrent GISTs treated at our institution between 2000 and 2017 were retrospectively analyzed. Genetic testing was performed before the initial drug administration to guide first-line imatinib therapy based on the primary mutation profile. In 64 imatinib-resistant patients, additional genetic testing was conducted on tissues obtained from resistant lesions. Treatment response and prognosis were compared across mutational profiles. Results: The most common primary mutation was KIT exon 11 (76.7%), followed by exon 9 (12.2%). Patients with exon 9 mutations showed superior progression-free survival with sunitinib than those with exon 11 mutations. Among patients with exon 11 primary mutations, secondary mutations were identified in 79.2%, predominantly in KIT exon 13/14 (47.9%) or 17/18 (31.3%). Sunitinib was more effective in patients with secondary exon 13/14 mutations, whereas regorafenib was significantly more effective in those with exon 17/18 mutations. Conclusions: Secondary KIT mutations play a crucial role in imatinib resistance and the efficacy of second- and third-line therapies. Genetic profiling at the initial diagnosis and at the time of resistance may provide more personalized and effective treatment strategies.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	102737
citation_title	Clinical impact of primary and secondary KIT mutations on the efficacy of molecular-targeted therapies in gastrointestinal stromal tumors
citation_author	Kawabata, Kota
	Takahashi, Tsuyoshi
	Nishida, Toshirou
	Kurokawa, Yukinori
	Yamamoto, Kazuyoshi
	Saito, Takuro
	Momose, Kota
	Yamashita, Kotaro
	Tanaka, Koji
	Makino, Tomoki
	Kawabata, Ryohei
	Takeno, Atsushi
	Nakajima, Kiyokazu
	Hirota, Seiichi
	Eguchi, Hidetoshi
	Doki, Yuichiro
citation_publisher	Springer
citation_language	English
citation_date	2025-07-23
citation_journal_title	Gastric Cancer
citation_volume	28
citation_issue	5
citation_firstpage	899
citation_lastpage	910
citation_doi	https://doi.org/10.1007/s10120-025-01639-1
citation_public_url	https://hdl.handle.net/11094/102737

Clinical impact of primary and secondary KIT mutations on the efficacy of molecular-targeted therapies in gastrointestinal stromal tumors

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