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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Glioblastoma (GBM) is the most aggressive primary brain tumor with limited therapeutic options and extremely poor prognosis. Aberrant activation of the receptor tyrosine kinase MET drives tumor progression, therapeutic resistance, and reduced survival, particularly in the mesenchymal GBM subtype. Given its crucial role in GBM recurrence and progression, we investigated the mechanisms of resistance to MET inhibition using patient-derived glioma-initiating cells (GICs) and orthotopic xenograft mouse models. GICs were treated with the MET inhibitor crizotinib to elucidate the mechanism of adaptive resistance. Prolonged MET inhibition induced a senescent-like phenotype in GICs, associated with downregulation of BNIP3, a mitochondrial protein regulating mitophagy. We showed that BNIP3 downregulation led to activation of mTOR signaling, promoting cellular survival and adaptive resistance. Combining crizotinib with the mTOR inhibitor everolimus effectively suppressed mTOR activity, reduced cell viability, and induced mitochondrial alterations, apoptosis, and necroptosis. In orthotopic GBM xenograft models, combined MET and mTOR inhibition significantly prolonged survival compared with single-agent treatments. Notably, sequential treatment\u2014crizotinib followed by everolimus\u2014further enhanced therapeutic efficacy. These effects were achieved without significant weight loss, supporting tolerability of the treatment regimen. Our findings identify the BNIP3-mTOR axis as a critical mediator of resistance to MET inhibition and demonstrate that combined inhibition of MET and mTOR exhibits significant synergy against GBM.<\/jats:p>","DOI":"10.3390\/ijms27177780","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"7780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting MET and mTOR Synergistically Overcomes Adaptive Resistance in Glioblastoma"],"prefix":"10.3390","volume":"27","author":[{"given":"Yunzhan","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Translational Medicine, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanif","family":"Khan","sequence":"additional","affiliation":[{"name":"Departments of Radiation Oncology, Penn State University, Hershey, PA 17033, USA"},{"name":"Departments of Neurosurgery, Penn State University, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyma","family":"Demirsoy","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery, Penn State University, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Younis","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery, Penn State University, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Valensi","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Penn State University, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Bernhardt","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongwu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell","family":"Machtay","sequence":"additional","affiliation":[{"name":"Departments of Radiation Oncology, Penn State University, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawit","family":"Aregawi","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery, Penn State University, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4877-5094","authenticated-orcid":false,"given":"Michael","family":"Glantz","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery, Penn State University, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Giglio","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Departments of Cellular and Molecular Physiology, Penn State University, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Schell","sequence":"additional","affiliation":[{"name":"Departments of Cell and Biological Systems, Penn State University, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vonn","family":"Walter","sequence":"additional","affiliation":[{"name":"Departments of Public Health Sciences, Penn State University, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasin","family":"Uzun","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Penn State University, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7153-4259","authenticated-orcid":false,"given":"Inan","family":"Olmez","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA 23298, USA"},{"name":"Massey Comprehensive Cancer Center, Virginia Commonwealth University, 401 College St, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1002\/cncr.20621","article-title":"Adult glioma incidence trends in the United States, 1977\u20132000","volume":"101","author":"Hess","year":"2004","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. 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