Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma

Rajappa S. Kenchappa, Athanassios Dovas, Michael G. Argenziano, Christian T. Meyer, Lauren E. Stopfer, Matei A. Banu, Brianna Pereira, Jessica Griffith, Afroz Mohammad, Surabhi Talele, Ashley Haddock, Natanael Zarco, William Elmquist, Forest White, Vito Quaranta, Peter Sims, Peter Canoll, Steven S. Rosenfeld

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number110991
JournalCell reports
Issue number12
StatePublished - Jun 21 2022


  • CP: Cancer
  • EGFR
  • STAT3
  • Src
  • glioblastoma
  • inhibitor
  • kinesin

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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