Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2023
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| Online Access: | https://hdl.handle.net/1721.1/147947 |
| _version_ | 1826194469781766144 |
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| author | 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 Haddock, Ashley Zarco, Natanael Elmquist, William White, Forest Quaranta, Vito Sims, Peter Canoll, Peter Rosenfeld, Steven S |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering 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 Haddock, Ashley Zarco, Natanael Elmquist, William White, Forest Quaranta, Vito Sims, Peter Canoll, Peter Rosenfeld, Steven S |
| author_sort | Kenchappa, Rajappa S |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T09:56:16Z |
| format | Article |
| id | mit-1721.1/147947 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:56:16Z |
| publishDate | 2023 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1479472023-02-08T03:39:25Z Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma 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 Haddock, Ashley Zarco, Natanael Elmquist, William White, Forest Quaranta, Vito Sims, Peter Canoll, Peter Rosenfeld, Steven S Massachusetts Institute of Technology. Department of Biological Engineering 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. 2023-02-07T19:00:36Z 2023-02-07T19:00:36Z 2022 2023-02-07T18:56:06Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/147947 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). en 10.1016/J.CELREP.2022.110991 Cell Reports Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Elsevier BV Cell Reports |
| spellingShingle | 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 Haddock, Ashley Zarco, Natanael Elmquist, William White, Forest Quaranta, Vito Sims, Peter Canoll, Peter Rosenfeld, Steven S Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma |
| title | Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma |
| title_full | Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma |
| title_fullStr | Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma |
| title_full_unstemmed | Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma |
| title_short | Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma |
| title_sort | activation of stat3 through combined src and egfr signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma |
| url | https://hdl.handle.net/1721.1/147947 |
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