{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:31:04Z","timestamp":1784806264570,"version":"3.55.0"},"reference-count":87,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation (RSF)","doi-asserted-by":"publisher","award":["24-25-00418"],"award-info":[{"award-number":["24-25-00418"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We previously demonstrated that the activation of FGFR signaling in GIST may be a mechanism of GIST resistance to imatinib mesylate (IM). We show here that IM-resistant GIST cells lacking secondary KIT mutations overexpress claudin-1 on both transcriptional and translational levels. In contrast, a knockdown of CLDN1 or inhibition of its activity by PDS-0330 effectively restored GIST\u2019s sensitivity to IM both in vitro and in vivo. This was evidenced by the increased expression of apoptotic markers (e.g., cleaved PARP and caspase-3) and the decreased proliferation rate of IM-resistant GIST T-1R cells treated with a combination of IM and PDS-0330 (or siRNA CLDN1). In concordance with these findings, a significant synergy was observed between IM and PDS-0330 in GIST T-1R cells. Importantly, decreased tumor size and weight were observed in IM-resistant GIST xenografts treated with a combination of IM and PDS-0330. Furthermore, the combined treatment of IM-resistant tumors induced an increase in intratumoral apoptosis and other changes, as defined by the histopathologic response rate. Based on the co-immunoprecipitation and immunofluorescence microscopy data, we also demonstrated the strong interaction pattern between CLDN1 and FGFR2. Of note, the inhibition or knockdown of CLDN1 effectively decreased the phosphorylation of FGFR2 and FRS-2, a well-known FGFR adaptor protein, thereby illustrating CLDN1\u2019s ability to regulate FGFR-signaling and thereby promote FGFR-mediated survival in KIT-inhibited GIST. Consequently, CLDN1 inhibition in GIST effectively disrupted the FGFR-mediated pathway and re-sensitized tumor cells to IM. In concordance with these data, molecular profiling of CLDN1-inhibited GIST T-1R cells illustrated a significant decrease in the majority of FGFR transcripts, including FGFR2, 3, and 4. Additionally, several FGFR ligands (e.g., FGF14, -19, and -23) were also down-regulated in PDS-0330-treated GIST. Notably, exogenous FGF-2 increased CLDN1 expression in a time-dependent manner. In contrast, pan-FGFR inhibitors effectively reduced CLDN1 levels in IM-resistant GIST T-1R cells, thereby illustrating a cross-talk between CLDN1- and FGFR-mediated pathways in IM-resistant GIST. Based on subcellular fractionation and immunofluorescence microscopy data, we also observed partial relocalization of CLDN1 into the cytoplasm in IM-resistant GIST. Notably, PDS-0330 effectively abrogated this relocalization, suggesting that changes in CLDN1 subcellular distribution might also impact GIST resistance to IM. Lastly, based on our small cohort clinical study (n = 24), we observed the increased expression of CLDN1 in most \u201chigh-risk\u201d primary GIST known to be associated with poor prognosis and aggressive behavior, thereby illustrating the prognostic value of increased CLDN1 expression in GIST and providing a further rationale to evaluate the effectiveness of CLDN1 inhibition for GIST therapy.<\/jats:p>","DOI":"10.3390\/ijms26178138","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T12:31:26Z","timestamp":1755865886000},"page":"8138","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Claudin-1 Contributes to Gastrointestinal Stromal Tumors (GIST) Resistance to Imatinib Mesylate (IM) via Regulation of FGFR-Signaling"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2415-1084","authenticated-orcid":false,"given":"Sergei","family":"Boichuk","sequence":"first","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"},{"name":"Department of Radiotherapy and Radiology, Faculty of Surgery, Russian Medical Academy of Continuous Professional Education, Moscow 125993, Russia"},{"name":"Central Research Laboratory, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9012-6525","authenticated-orcid":false,"given":"Firyuza","family":"Bikinieva","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5449-4435","authenticated-orcid":false,"given":"Pavel","family":"Dunaev","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0293-2974","authenticated-orcid":false,"given":"Aigul","family":"Galembikova","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8213-427X","authenticated-orcid":false,"given":"Ekaterina","family":"Mikheeva","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Valeeva","sequence":"additional","affiliation":[{"name":"Central Research Laboratory, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0490-0383","authenticated-orcid":false,"given":"Shinjit","family":"Mani","sequence":"additional","affiliation":[{"name":"Department of Pathology, Kazan State Medical University, Kazan 420012, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8348-6760","authenticated-orcid":false,"given":"Natalia","family":"Khromova","sequence":"additional","affiliation":[{"name":"Cytogenetics Laboratory, Carcinogenesis Institute, N.N. Blokhin National Medical Research Center of Oncology, Moscow 115458, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2078-4274","authenticated-orcid":false,"given":"Pavel","family":"Kopnin","sequence":"additional","affiliation":[{"name":"Cytogenetics Laboratory, Carcinogenesis Institute, N.N. Blokhin National Medical Research Center of Oncology, Moscow 115458, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6292-6560","authenticated-orcid":false,"given":"Leyla","family":"Shigapova","sequence":"additional","affiliation":[{"name":"Regulatory Genomics Research Center, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0019-2076","authenticated-orcid":false,"given":"Ruslan","family":"Deviatiiarov","sequence":"additional","affiliation":[{"name":"Regulatory Genomics Research Center, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia"},{"name":"Endocrinology Research Centre, Institute of Personalized Medicine, Moscow 117292, Russia"},{"name":"Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2339-261X","authenticated-orcid":false,"given":"Elena","family":"Shagimardanova","sequence":"additional","affiliation":[{"name":"LIFT\u2014Life Improvement by Future Technologies Institute, Moscow 121205, Russia"},{"name":"Genomics and Bioimaging Core Facility, Moscow 121205, Russia"},{"name":"Loginov Moscow Clinical Scientific Center, Moscow 111123, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2595-353X","authenticated-orcid":false,"given":"Sergey","family":"Ryzhkin","sequence":"additional","affiliation":[{"name":"Department of Radiotherapy and Radiology, Faculty of Surgery, Russian Medical Academy of Continuous Professional Education, Moscow 125993, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Sabirov","sequence":"additional","affiliation":[{"name":"Tatarstan Cancer Center, Kazan 420029, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"ref_1","first-page":"8118","article-title":"KIT Activation Is a Ubiquitous Feature of Gastrointestinal Stromal Tumors","volume":"61","author":"Rubin","year":"2001","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1126\/science.1079666","article-title":"PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors","volume":"299","author":"Heinrich","year":"2003","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1126\/science.279.5350.577","article-title":"Gain-of-Function Mutations of c-Kit in Human Gastrointestinal Stromal Tumors","volume":"279","author":"Hirota","year":"1998","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1002\/cncr.24944","article-title":"The Role of High-dose Imatinib in the Management of Patients with Gastrointestinal Stromal Tumor","volume":"116","author":"Gronchi","year":"2010","journal-title":"Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13045-020-01026-6","article-title":"The Management of Metastatic GIST: Current Standard and Investigational Therapeutics","volume":"14","author":"Kelly","year":"2021","journal-title":"J. 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