Title | Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Kenchappa RS, Dovas A, Argenziano MG, Meyer CT, Stopfer LE, Banu MA, Pereira B, Griffith J, Mohammad A, Talele S, Haddock A, Zarco N, Elmquist W, White F, Quaranta V, Sims P, Canoll P, Rosenfeld SS |
Journal | Cell Rep |
Volume | 39 |
Issue | 12 |
Pagination | 110991 |
Date Published | 2022 Jun 21 |
ISSN | 2211-1247 |
Keywords | Animals, Antimitotic Agents, Cell Line, Tumor, ErbB Receptors, Glioblastoma, Kinesins, Mice, Signal Transduction, STAT3 Transcription Factor |
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. |
DOI | 10.1016/j.celrep.2022.110991 |
Alternate Journal | Cell Rep |
PubMed ID | 35732128 |
Grant List | R38 CA231577 / CA / NCI NIH HHS / United States U54 CA210180 / CA / NCI NIH HHS / United States T32 ES007020 / ES / NIEHS NIH HHS / United States U01 CA238720 / CA / NCI NIH HHS / United States |