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 I Griffith, Afroz Shareef Mohammad, Surabhi M Talele, Ashley Haddock, Natanael Zarco, William Elmquist, Forest White, Vito Quaranta, Peter Sims, Peter Canoll, Steven S. Rosenfeld

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number110991
JournalCell reports
Volume39
Issue number12
DOIs
StatePublished - Jun 21 2022

Bibliographical note

Funding Information:
We wish to thank Dr. Justin D. Lathia (Lerner Research Institute of the Cleveland Clinic Foundation) for his gift of L1 cells; Drs. Alfredo Quiñones-Hinojosa and Hugo Guerrero-Cazares (Mayo Clinic Florida) for their gift of GBM1A, GBM120, and GBM612 cells; and Ms. Amanda Luu, Ms. Rita West, and Dr. Montserrat Lara-Velazquez for their excellent technical assistance. S.S.R. is supported by NIH grants NS073610 , NS118513 , NS119714 , and CA210910 and by a Translational Adult Glioma Award from the Ben and Catherine Ivy Foundation. P.C. is supported by NIH grants NS073610 and NS118513 . P.S. is supported by NIH grant NS103473 and an Emerging Leader Award from the Mark Foundation for Cancer Research. W.E. is supported by NIH grant NS073610 . R.S.K. is supported by NIH grant NS118513 . V.Q. is supported by NIH grants CA217450 and CA215845 . F.W. is supported by NIH grants U54CA210180 and U01CA238720 . L.E.S. was supported by NIH T32ES007020 .

Funding Information:
We wish to thank Dr. Justin D. Lathia (Lerner Research Institute of the Cleveland Clinic Foundation) for his gift of L1 cells; Drs. Alfredo Quiñones-Hinojosa and Hugo Guerrero-Cazares (Mayo Clinic Florida) for their gift of GBM1A, GBM120, and GBM612 cells; and Ms. Amanda Luu, Ms. Rita West, and Dr. Montserrat Lara-Velazquez for their excellent technical assistance. S.S.R. is supported by NIH grants NS073610, NS118513, NS119714, and CA210910 and by a Translational Adult Glioma Award from the Ben and Catherine Ivy Foundation. P.C. is supported by NIH grants NS073610 and NS118513. P.S. is supported by NIH grant NS103473 and an Emerging Leader Award from the Mark Foundation for Cancer Research. W.E. is supported by NIH grant NS073610. R.S.K. is supported by NIH grant NS118513. V.Q. is supported by NIH grants CA217450 and CA215845. F.W. is supported by NIH grants U54CA210180 and U01CA238720. L.E.S. was supported by NIH T32ES007020. Conception and design, R.S.K. A.D. S.S.R. P.C. V.Q. C.T.M. F.W. and P.S.; development of methodology, R.S.K. A.D. S.S.R. V.Q. P.S. W.E. C.T.M. M.A.B. M.G.A. L.E.S. and F.W.; acquisition of data, R.S.K. A.D. P.S. W.E. M.A.B. M.G.A. L.E.S. F.W. B.P. J.G. A.M. and S.T.; analysis and interpretation of data, R.S.K. A.D. S.S.R. P.S. M.A.B. M.G.A. C.T.M. L.E.S. J.G. A.M. S.T. and F.W. The authors declare no competing interests.

Publisher Copyright:
© 2022 The Author(s)

Keywords

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

PubMed: MeSH publication types

  • Journal Article

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