Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma
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1-s2.0-S221112472200777X-main.pdf
Description
Published version
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5.2 MB
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Adobe PDF
Checksum (MD5)
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Author(s)
Kenchappa, Rajappa S
Dovas, Athanassios
Argenziano, Michael G
Meyer, Christian T
Stopfer, Lauren E
Banu, Matei A
Pereira, Brianna
Griffith, Jessica
Mohammad, Afroz
Talele, Surabhi
Date Issued
2022
Journal
Cell Reports
Publisher
Elsevier BV
Citation
Kenchappa, Rajappa S, Dovas, Athanassios, Argenziano, Michael G, Meyer, Christian T, Stopfer, Lauren E et al. 2022. "Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma." Cell Reports, 39 (12).
Version
Final published version
Abstract
Inhibitors of the mitotic kinesin Kif11 are anti-mitotics that, unlike vinca alkaloids or taxanes, do not disrupt microtubules and are not neurotoxic. However, development of resistance has limited their clinical utility. While resistance to Kif11 inhibitors in other cell types is due to mechanisms that prevent these drugs from disrupting mitosis, we find that in glioblastoma (GBM), resistance to the Kif11 inhibitor ispinesib works instead through suppression of apoptosis driven by activation of STAT3. This form of resistance requires dual phosphorylation of STAT3 residues Y705 and S727, mediated by SRC and epidermal growth factor receptor (EGFR), respectively. Simultaneously inhibiting SRC and EGFR reverses this resistance, and combined targeting of these two kinases in vivo with clinically available inhibitors is synergistic and significantly prolongs survival in ispinesib-treated GBM-bearing mice. We thus identify a translationally actionable approach to overcoming Kif11 inhibitor resistance that may work to block STAT3-driven resistance against other anti-cancer therapies as well.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1016/J.CELREP.2022.110991
