Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma

Dorothy Benton; Hoi Yee Chow; Sofiia Karchugina; Jonathan Chernoff

doi:10.1371/journal.pone.0305121

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Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma

Journal article

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Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma

Dorothy Benton, Hoi Yee Chow, Sofiia Karchugina and Jonathan Chernoff

PloS one, v 19(7), pe0305121

31 Jul 2024

DOI: https://doi.org/10.1371/journal.pone.0305121

PMID: 39083549

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Abstract

Adaptor Proteins, Signal Transducing - genetics

Adaptor Proteins, Signal Transducing - metabolism

Apoptosis - drug effects

Cell Line, Tumor

Cell Proliferation - drug effects

DNA-Binding Proteins - genetics

DNA-Binding Proteins - metabolism

Drug Synergism

Hippo Signaling Pathway

Humans

Neurilemmoma - genetics

Neurilemmoma - metabolism

Neurilemmoma - pathology

Neurofibromatosis 2 - genetics

Neurofibromatosis 2 - metabolism

Neurofibromin 2 - deficiency

Neurofibromin 2 - genetics

Neurofibromin 2 - metabolism

p21-Activated Kinases - antagonists & inhibitors

p21-Activated Kinases - genetics

p21-Activated Kinases - metabolism

Protein Kinase Inhibitors - pharmacology

Protein Serine-Threonine Kinases - antagonists & inhibitors

Protein Serine-Threonine Kinases - genetics

Protein Serine-Threonine Kinases - metabolism

Signal Transduction - drug effects

Transcription Factors - genetics

Transcription Factors - metabolism

YAP-Signaling Proteins - genetics

YAP-Signaling Proteins - metabolism

Neurofibromatosis type 2 is a genetic disorder that results in the formation and progressive growth of schwannomas, ependymomas, and/or meningiomas. The NF2 gene encodes the Merlin protein, which links cell cortical elements to the actin cytoskeleton and regulates a number of key enzymes including Group I p21-activated kinases (PAKs), the Hippo-pathway kinase LATS, and mTORC. While PAK1 and PAK2 directly bind Merlin and transmit proliferation and survival signals when Merlin is mutated or absent, inhibition of Group 1 PAKs alone has not proven sufficient to completely stop the growth of NF2-deficient meningiomas or schwannomas in vivo, suggesting the need for a second pathway inhibitor. As the Hippo pathway is also activated in NF2-deficient cells, several inhibitors of the Hippo pathway have recently been developed in the form of YAP-TEAD binding inhibitors. These inhibitors prevent activation of pro-proliferation and anti-apoptotic Hippo pathway effectors. In this study, we show that PAK inhibition slows cell proliferation while TEAD inhibition promotes apoptotic cell death. Finally, we demonstrate the efficacy of PAK and TEAD inhibitor combinations in several NF2-deficient Schwannoma cell lines.

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Title: Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma
Creators: Dorothy Benton - Drexel University, Biochemistry and Molecular Biology
Hoi Yee Chow - Fox Chase Cancer Center
Sofiia Karchugina - Fox Chase Cancer Center
Jonathan Chernoff - Fox Chase Cancer Center
Publication Details: PloS one, v 19(7), pe0305121
Publisher: PLOS
Resource Type: Journal article
Language: English
Academic Unit: Biochemistry and Molecular Biology
Web of Science ID: WOS:001293346700034
Scopus ID: 2-s2.0-85200129701
Other Identifier: 991021906507504721

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Collaboration types: Domestic collaboration
Web of Science research areas: Oncology

Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma

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Abstract

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UN Sustainable Development Goals (SDGs)

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