Identifying and exploiting combinatorial synthetic lethality by characterizing adaptive kinome rewiring of EGFRvIII-driven glioblastoma

dc.contributor.authorLin, Benjamin
dc.contributor.authorShelton, Abigail K.
dc.contributor.authorSmithberger, Erin
dc.contributor.authorZiebro, Julia
dc.contributor.authorSkinner, Kasey R.
dc.contributor.authorBash, Ryan E.
dc.contributor.authorKirkman, Richard
dc.contributor.authorStamper, Allie
dc.contributor.authorButler, Madison
dc.contributor.authorFlores, Alex
dc.contributor.authorAngus, Steven P.
dc.contributor.authorEast, Michael P.
dc.contributor.authorCloughesy, Timothy F.
dc.contributor.authorNathanson, David A.
dc.contributor.authorBerens, Michael E.
dc.contributor.authorSarkaria, Jann N.
dc.contributor.authorBinder, Zev A.
dc.contributor.authorO’Rourke, Donald M.
dc.contributor.authorHowton, Timothy C.
dc.contributor.authorLasseigne, Brittany N.
dc.contributor.authorWilley, Christopher D.
dc.contributor.authorJohnson, Gary L.
dc.contributor.authorHjelmeland, Anita B.
dc.contributor.authorFurnari, Frank B.
dc.contributor.authorMiller, C. Ryan
dc.contributor.departmentPediatrics, School of Medicine
dc.date.accessioned2025-07-15T11:53:42Z
dc.date.available2025-07-15T11:53:42Z
dc.date.issued2025-06-28
dc.description.abstractGBM is an aggressive primary malignant brain tumor that has a poor prognosis. Molecular characterization of GBM has shown that EGFR mutations are present in over 50% of tumors. However, EGFR inhibitors have not shown clinical efficacy in contrast to other EGFR-driven neoplasms due to the unique EGFR biology found in GBM. Upfront combinatorial therapy featuring EGFR tyrosine kinase inhibitors (TKI) may overcome these challenges. To identify combinatorial drug targets within the kinome, we temporally characterized drug-induced kinome rewiring in isogenic, genetically engineered Cdkn2a-deleted mouse astrocytes expressing human EGFRvIII. We utilize RNA sequencing and multiplex inhibitor beads, coupled with mass spectrometry, to demonstrate that kinome rewiring exhibits both shared and unique kinases after acquired resistance develops to EGFR TKI, despite using models with a common genetic background. Additionally, we noted that kinases altered in the acute setting are distinct from those in acquired resistance. By identifying kinome vulnerabilities throughout the acute, dynamic drug response process, we generated a kinase signature associated with EGFR inhibition. Further molecular interrogation of signature genes revealed that drug treatment induces an unexpected increase in Cdk6 protein, but not mRNA, despite live cell imaging and transcriptomic evidence indicating decreased proliferation. Survival experiments with orthotopic allografts show that upfront combination inhibition of Cdk6, using abemaciclib, and EGFR, using neratinib, significantly prolonged median survival compared to neratinib alone. Our findings suggest that identifying and inhibiting targets with synthetic lethality in the upfront combinatorial setting is a viable approach for precision oncology and may help provide an avenue to overcome the resistance mechanisms that contributed to the failures of EGFR as a molecular target in GBM.
dc.eprint.versionFinal published version
dc.identifier.citationLin B, Shelton AK, Smithberger E, et al. Identifying and exploiting combinatorial synthetic lethality by characterizing adaptive kinome rewiring of EGFRvIII-driven glioblastoma. Acta Neuropathol Commun. 2025;13(1):143. Published 2025 Jun 28. doi:10.1186/s40478-025-02068-y
dc.identifier.urihttps://hdl.handle.net/1805/49471
dc.language.isoen_US
dc.publisherSpringer Nature
dc.relation.isversionof10.1186/s40478-025-02068-y
dc.relation.journalActa Neuropathologica Communications
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePMC
dc.subjectEGFR
dc.subjectGlioblastoma
dc.subjectSynthetic lethality
dc.subjectKin­ome rewiring
dc.subjectUpfront combinatorial therapy
dc.titleIdentifying and exploiting combinatorial synthetic lethality by characterizing adaptive kinome rewiring of EGFRvIII-driven glioblastoma
dc.typeArticle
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