RAPID resistance to BET inhibitors is mediated by FGFR1 in glioblastoma.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Glioblastoma*/drug therapy ; Glioblastoma*/metabolism ; Glioblastoma*/pathology ; Glioblastoma*/genetics ; Receptor, Fibroblast Growth Factor, Type 1*/antagonists & inhibitors ; Receptor, Fibroblast Growth Factor, Type 1*/metabolism ; Receptor, Fibroblast Growth Factor, Type 1*/genetics ; Drug Resistance, Neoplasm*/drug effects ; Cell Proliferation*/drug effects ; Brain Neoplasms*/drug therapy ; Brain Neoplasms*/metabolism ; Brain Neoplasms*/pathology ; Bromodomain Containing Proteins*; Humans ; Cell Line, Tumor ; Animals ; Mice ; Xenograft Model Antitumor Assays ; Proteomics/methods ; Proteins/metabolism ; Proteins/antagonists & inhibitors

Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that intrinsic resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Additionally, small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.
(© 2024. The Author(s).)

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EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1)
EC 2.7.10.1 (FGFR1 protein, human)
0 (bromodomain and extra-terminal domain protein, human)
0 (Proteins)
0 (Bromodomain Containing Proteins)

Date Created: 20240423 Date Completed: 20240424 Latest Revision: 20240502

20240503

PMC11039727

10.1038/s41598-024-60031-8

38654040