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Cited by 21Glioma Diagnosis and TreatmentCancer, Hypoxia, and MetabolismPI3K/AKT/mTOR signaling in cancer

MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma

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Kenchappa, Rajappa S., Radnai, Laszlo, Young, Erica J., Zarco, Natanael, Lin, Li, Dovas, Athanassios, Meyer, Christian T., Haddock, Ashley +10 more·2025·Cell
DOI 10.1016/j.cell.2025.05.019PMC PMC12354127
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Abstract

Glioblastoma (GBM) is the most lethal of primary brain tumors. Here, we report our studies of MT-125, a small-molecule inhibitor of non-muscle myosin II. MT-125 has high brain penetrance and an excellent safety profile, blocks GBM invasion and cytokinesis, and prolongs survival in murine GBM models. By impairing mitochondrial fission, MT-125 increases redox stress and consequent DNA damage, and it synergizes with radiotherapy. MT-125 also induces oncogene addiction to PDGFR signaling through a mechanism that is driven by redox stress, and it synergizes with FDA-approved PDGFR and mTOR inhibitors in vitro. Consistent with this, we find that combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor, significantly improves survival in orthotopic GBM models over either drug alone. Our results demonstrate that MT-125 is a first-in-class therapeutic that has strong clinical potential for the treatment of GBM.

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Cited by

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Authors
Kenchappa, R. S., Radnai, L., Young, E. J., Zarco, N., Lin, L., Dovas, A., Meyer, C. T., Haddock, A., Hall, A., Toth, K., Canoll, P., Nagaiah, N. K. H., Rumbaugh, G., Cameron, M. D., Kamenecka, T. M., Griffin, P. R., Miller, C. A., & Rosenfeld, S. S.
Affiliations
  • Mayo Clinic in Florida (US)
  • Scripps Research Institute (US)
  • Mayo Clinic (US)
  • Columbia University Irving Medical Center (US)
  • University of Colorado Boulder (US)
Corresponding author
  • Kenchappa, Rajappa S.
  • Miller, Courtney A.
  • Rosenfeld, Steven S.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2025-08
Volume
188
Issue
17
Pages
4622-4639.e19
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2025.05.019
PMC
PMC12354127
OpenAlex
W4411179623
Cited by
21
References
3
Citations by year
2026: 11 · 2025: 9 · 2024: 1
FWCI
11.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institute on Drug Abuse
  • Ben and Catherine Ivy Foundation (UH3NS096833, R01DA049544)
  • National Cancer Institute (CA250481, CA210910, CA251313)
  • National Institute of Allergy and Infectious Diseases (1K99AI175656, R42CA278293)
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (NS119714, NS118513, NS073610)
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
non-muscle myosin II, glioblastoma, mitochondrial fission, redox stress, DNA damage, tumor invasion, cytokinesis, PDGFR signaling, oncogene addiction, radiotherapy synergy, sunitinib, paxalisib, PI3K/mTOR inhibition, combination therapy

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