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ROLE OF TGLI1 IN RESISTANCE OF GLIOBLASTOMA TO CDK4/6 INHIBITION

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abstract
Glioblastoma (GBM) is the most frequent and aggressive brain cancer in adults. Standard-of-care therapy for GBM is the combination of surgery, radiation therapy, and temozolomide. However, therapeutic resistance is common and can be attributed to tumor heterogeneity, so new effective therapies are urgently required. CDK4/6 are cell-cycle regulatory proteins aberrantly expressed in GBM and promote tumor proliferation, so CDK4/6 inhibitors are potential therapeutic agents for GBM. However, resistance to these compounds limits their clinical effectiveness. Our laboratory discovered an alternative splice variant of glioma-associated oncogene homolog 1 (GLI1) in GBM, termed truncated GLI1 (TGLI1), that is a gain-of-function GLI1 transcription factor and a terminal effector of the SHH pathway. Herein, we identify TGLI1 as a novel mediator of CDK4/6 inhibitor resistance in GBM. TGLI1 is co-expressed with CDK4/6 in GBM specimens and cell lines. TGLI1 overexpression renders GBM cells and glioma stem cells (GSCs) more resistant to CDK4/6 inhibitors, abemaciclib and palbociclib. Furthermore, targeting TGLI1-expressing cells using ketoconazole (KCZ) sensitizes TGLI1-positive GBM cells and GSCs to CDK4/6 inhibitors in vitro. Combination of KCZ and the CDK4/6 inhibitor abemaciclib suppresses intracranial GBM tumor growth in vivo. The analyses of the brain sections with GBM xenografts by immunohistochemistry and TUNEL assay demonstrate the combination therapy to effectively suppress cell proliferation, angiogenesis, and induce apoptosis in vivo. Flow cytometry analyses demonstrate the KCZ-abemaciclib combination therapy effectively induces cell cycle arrest and apoptosis in vitro. Mechanistically, TGLI1 promotes CDK6 expression in CDK6/Rb-positive GBM cells and FOXM1 protein expression, a nuclear effector of the CDK4/6 pathway, in Rb-deficient GBM cells. Collectively, our study demonstrates the novel role of TGLI1 in CDK4/6 inhibitor resistance and validates the combination of KCZ and abemaciclib as a potential strategy to overcome TGLI1-mediated CDK4/6 inhibitor resistance in GBM.
subject
contributor
Yu, Yang (author)
Lo, Hui-Wen (committee chair)
Xing, Fei (committee member)
Gmeiner, William H (committee member)
Strowd, Roy E (committee member)
date
2021-06-03T08:35:45Z (accessioned)
2021 (issued)
degree
Biomedical Science – MS (discipline)
2023-06-02 (liftdate)
embargo
2023-06-02 (terms)
identifier
http://hdl.handle.net/10339/98776 (uri)
language
en (iso)
publisher
Wake Forest University
title
ROLE OF TGLI1 IN RESISTANCE OF GLIOBLASTOMA TO CDK4/6 INHIBITION
type
Thesis

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