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

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

  • Acta Neuropathol Commun. 2025 Jun 28;13(1):143. doi: 10.1186/s40478-025-02068-y.
Benjamin Lin # 1 2,  Abigail K Shelton # 2,  Erin Smithberger 2,  Julia Ziebro 2,  Kasey R Skinner 2,  Ryan E Bash 2,  Richard Kirkman 2,  Allie Stamper 2,  Madison Butler 3,  Alex Flores 4,  Steven P Angus 5,  Michael P East 6,  Timothy F Cloughesy 7,  David A Nathanson 8,  Michael E Berens 9,  Jann N Sarkaria 10,  Zev A Binder 11,  Donald M O'Rourke 11,  Timothy C Howton 12,  Brittany N Lasseigne 12 13 14,  Christopher D Willey 13 15,  Gary L Johnson 6,  Anita B Hjelmeland 12 13 14,  Frank B Furnari 16,  C Ryan Miller 17 18 19
Affiliations

Affiliations

  • 1 Medical Scientist Training Program, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 2 Division of Neuropathology, Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, WTI 410C, 1824 6th Avenue South, Birmingham, AL, 35294-3300, USA.
  • 3 Department of Biology, University of North Carolina, Chapel Hill, NC, USA.
  • 4 University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 5 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 6 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 7 Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • 8 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • 9 Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
  • 10 Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
  • 11 Department of Neurosurgery and Glioblastoma Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 12 Department of Cell, Developmental and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 13 O'Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 14 Comprehensive Neuroscience Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 15 Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 16 Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, San Diego, CA, USA.
  • 17 Division of Neuropathology, Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, WTI 410C, 1824 6th Avenue South, Birmingham, AL, 35294-3300, USA. ryanmiller@uabmc.edu.
  • 18 O'Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. ryanmiller@uabmc.edu.
  • 19 Comprehensive Neuroscience Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. ryanmiller@uabmc.edu.
  • # Contributed equally.
PMID: 40581663 DOI: 10.1186/s40478-025-02068-y
Abstract

GBM 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.

Keywords

EGFR; Glioblastoma; Kinome rewiring; Synthetic lethality; Upfront combinatorial therapy.

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