Advisor(s)
C Ryan Miller
Committee Member(s)
Anita Hjelmeland
Brittany Lasseigne
Christopher Willey
Frank Furnari
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Pathology
Date of Award
9-11-2025
Abstract
Glioblastoma (GBM) is an aggressive primary malignant brain tumor with a poor progno-sis with a 5-year survival of 5%. GBM has been molecularly characterized through multiple large scale genomic studies starting off with The Cancer Genome Atlas (TCGA). These studies have revealed that EGFR mutations are the most prevalent oncogenic mutation pre-sent in these tumors. The most common EGFR mutation is EGFRvIII, an interstitial dele-tion of exons 2-7. Due to its presence as an activating mutation in over 50% of GBM, EGFR is an attractive target for precision oncology approaches. Currently, a precision on-cology approach is not included in the standard of care consisting of maximal safe surgical resection, radiation therapy, and chemotherapy. Clinical trials targeting EGFR with small molecule inhibitors or biologics have been unsuccessful in GBM despite showing clinical efficacy in other EGFR-driven neoplasms like non-small cell lung cancers (NSCLC). The failures of these clinical trials can be partially attributed to the unique EGFR biology present in GBM. In contrast to EGFR-driven NSCLC, EGFR mutations in GBM concentrate in the extracellular domain and gatekeeper mutations that provide inherent resistance to EGFR targeting therapeutics have not been observed. Here we leveraged the knowledge gained in EGFR biology since those early failed clinical trials to design a precision oncology ap-proach targeting EGFR. We believe that upfront combinatorial therapy that inhibits EGFR with another synthetically lethal target, we can prolong survival. To investigate this, we generated an isogenic model of the EGFRvIII kinome, using a genetically engineered mouse astrocyte cell line. To better understand the drug induced kinome rewiring, we tem-porally characterized cell lines after acquire resistance to EGFR tyrosine kinase inhibitors (TKI) develops and acutely within 48 hours of drug treatment with kinase proteomics and transcriptomics. Proteo-transcriptomic analysis revealed an unexpected acute increase in Cdk6 protein, but not mRNA despite a decrease in proliferation after EGFR TKI treatment. Two cohorts of orthotopic allografts show that co-inhibition of EGFRvIII and Cdk6 signif-icantly prolongs survival. Together, these results show that upfront combinatorial therapy exploiting synthetic lethality is a viable approach to prolong survival in EGFR-driven GBM.
ProQuest ID
Recommended Citation
Lin, Benjamin, "Modelling And Interrogating The Kinome Of Egfr-Driven Glioblastoma" (2025). All ETDs from UAB. 7348.
https://digitalcommons.library.uab.edu/etd-collection/7348
