RAPID resistance to BET inhibitors is mediated by FGFR1 in glioblastoma

Anna M. Jermakowicz; Alison M. Kurimchak; Katherine J. Johnson; Florence Bourgain-Guglielmetti; Simon Kaeppeli; Maurizio Affer; Hari Pradhyumnan; Robert K. Suter; Winston Walters; Maria Cepero; James S. Duncan; Nagi G. Ayad

doi:10.1038/s41598-024-60031-8

RAPID resistance to BET inhibitors is mediated by FGFR1 in glioblastoma

Anna M. Jermakowicz, Alison M. Kurimchak, Katherine J. Johnson, Florence Bourgain-Guglielmetti, Simon Kaeppeli, Maurizio Affer, Hari Pradhyumnan, Robert K. Suter, Winston Walters, Maria Cepero, James S. Duncan, Nagi G. Ayad

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.

Original language	English
Article number	9284
Pages (from-to)	9284
Journal	Scientific Reports
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41598-024-60031-8
State	Published - Mar 23 2024

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41598-024-60031-8

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title = "RAPID resistance to BET inhibitors is mediated by FGFR1 in glioblastoma",

abstract = "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.",

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author = "Jermakowicz, {Anna M.} and Kurimchak, {Alison M.} and Johnson, {Katherine J.} and Florence Bourgain-Guglielmetti and Simon Kaeppeli and Maurizio Affer and Hari Pradhyumnan and Suter, {Robert K.} and Winston Walters and Maria Cepero and Duncan, {James S.} and Ayad, {Nagi G.}",

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doi = "10.1038/s41598-024-60031-8",

language = "English",

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T1 - RAPID resistance to BET inhibitors is mediated by FGFR1 in glioblastoma

AU - Jermakowicz, Anna M.

AU - Kurimchak, Alison M.

AU - Johnson, Katherine J.

AU - Bourgain-Guglielmetti, Florence

AU - Kaeppeli, Simon

AU - Affer, Maurizio

AU - Pradhyumnan, Hari

AU - Suter, Robert K.

AU - Walters, Winston

AU - Cepero, Maria

AU - Duncan, James S.

AU - Ayad, Nagi G.

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024/3/23

Y1 - 2024/3/23

N2 - 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.

AB - 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.

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KW - Drug Resistance, Neoplasm/drug effects

KW - Glioblastoma/drug therapy

KW - Humans

KW - Mice

KW - Proteins/metabolism

KW - Proteomics/methods

KW - Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors

KW - Xenograft Model Antitumor Assays

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JO - Scientific Reports

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ER -

RAPID resistance to BET inhibitors is mediated by FGFR1 in glioblastoma

Abstract

Keywords

UN SDGs

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