Evidence map›Paper›PMID 42737677›Full record

ArticleInternational journal of molecular sciences2026

Targeting MET and mTOR Synergistically Overcomes Adaptive Resistance in Glioblastoma.

Yunzhan Li, Hanif Khan, Seyma Demirsoy, Muhammad Younis, Guilan Shi, Hannah Valensi, William Bernhardt, Jeongwu Lee, Mitchell Machtay, Dawit Aregawi and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in International journal of molecular sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Yunzhan LiInstitute of Translational Medicine, China Pharmaceutical University, Nanjing 210009, China.
Hanif KhanDepartments of Radiation Oncology, Penn State University, Hershey, PA 17033, USA.
Seyma DemirsoyDepartments of Neurosurgery, Penn State University, Hershey, PA 17033, USA.
Muhammad YounisDepartments of Neurosurgery, Penn State University, Hershey, PA 17033, USA.
Guilan ShiDepartment of Neurosurgery, Virginia Commonwealth University, Richmond, VA 23298, USA.
Hannah ValensiDepartments of Pediatrics, Penn State University, Hershey, PA 17033, USA.
William BernhardtDepartment of Neurosurgery, Virginia Commonwealth University, Richmond, VA 23298, USA.
Jeongwu LeeDepartment of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Mitchell MachtayDepartments of Radiation Oncology, Penn State University, Hershey, PA 17033, USA.
Dawit AregawiDepartments of Neurosurgery, Penn State University, Hershey, PA 17033, USA.
Michael GlantzDepartments of Neurosurgery, Penn State University, Hershey, PA 17033, USA.ORCID 0000-0003-4877-5094
Pierre GiglioDepartment of Neurology, Ohio State University, Columbus, OH 43210, USA.
Shengyu YangDepartments of Cellular and Molecular Physiology, Penn State University, Hershey, PA 17033, USA.
Todd SchellDepartments of Cell and Biological Systems, Penn State University, Hershey, PA 17033, USA.
Vonn WalterDepartments of Public Health Sciences, Penn State University, Hershey, PA 17033, USA.
Yasin UzunDepartments of Pediatrics, Penn State University, Hershey, PA 17033, USA.
Inan OlmezDepartment of Neurosurgery, Virginia Commonwealth University, Richmond, VA 23298, USA.ORCID 0000-0002-7153-4259

Funding

Developing an image-guided therapeutic strategy to effectively target metabolic reprogramming in glioblastomaR21NS123606 · NINDS · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · PI OLMEZ, INAN · 2022 to 2023
$446k
Congressionally Directed Medical Research Programs W81XWH-20-1-0046Congressionally Directed Medical Research Programs W81XWH-21-1-0268NIH HHS 1R21NS123606-01NINDS NIH HHS R21 NS123606
6 · The paper itself

Abstract

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-crizotinib followed by everolimus-further 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.

Indexed as

Brain NeoplasmsDrug Resistance, NeoplasmGlioblastomaMTOR InhibitorsProto-Oncogene Proteins c-metTOR Serine-Threonine KinasesAnimalsApoptosisCell Line, TumorCell SurvivalCrizotinibDrug SynergismEverolimusHumansMembrane ProteinsMiceBNIP3 protein, humanCrizotinibEverolimusMembrane ProteinsMET protein, humanMitochondrial ProteinsMTOR InhibitorsMTOR protein, humanProtein Kinase InhibitorsProto-Oncogene ProteinsProto-Oncogene Proteins c-metTOR Serine-Threonine KinasesBNIP3crizotinibeverolimusGlioblastomaMETmTOR

Identifiers

PMID42737677
PMCPMC13565985

What OpenQuestion holds

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Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.