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

Autor: Jermakowicz AM; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20007, USA., Kurimchak AM; Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA., Johnson KJ; Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA., Bourgain-Guglielmetti F; Department of Neurosurgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Fl, 33136, USA., Kaeppeli S; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20007, USA., Affer M; Department of Neurosurgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Fl, 33136, USA., Pradhyumnan H; Department of Neurosurgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Fl, 33136, USA., Suter RK; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20007, USA., Walters W; Department of Neurosurgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Fl, 33136, USA., Cepero M; Department of Neurosurgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Fl, 33136, USA., Duncan JS; Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA., Ayad NG; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20007, USA. na853@georgetown.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Apr 23; Vol. 14 (1), pp. 9284. Date of Electronic Publication: 2024 Apr 23.
DOI: 10.1038/s41598-024-60031-8
Abstrakt: 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).)
Databáze: MEDLINE
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