Journal Article

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

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

2024

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Actin / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Amino acids / Apoptosis / Apoptosis - drug effects / Biology and Life Sciences / Biotechnology industry / Brain cancer / Cell activation / Cell death / Cell Line, Tumor / Cell lines / Cell proliferation / Cell Proliferation - drug effects / Cytoskeleton / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Drug dosages / Drug Synergism / Drug therapy / Enzymes / Ethylenediaminetetraacetic acid / Genes / Genetic disorders / GTP-binding protein / Hippo Signaling Pathway / Humans / In vivo methods and tests / Inhibitors / Kinases / Medicine and Health Sciences / Merlin protein / Muscle proteins / Neurilemmoma - genetics / Neurilemmoma - metabolism / Neurilemmoma - pathology / Neurofibromatosis / Neurofibromatosis 2 / Neurofibromatosis 2 - genetics / Neurofibromatosis 2 - metabolism / Neurofibromin 2 / Neurofibromin 2 - deficiency / Neurofibromin 2 - genetics / Neurofibromin 2 - metabolism / p21-Activated Kinases - antagonists & inhibitors / p21-Activated Kinases - genetics / p21-Activated Kinases - metabolism / Penicillin / Protein Kinase Inhibitors - pharmacology / Protein Serine-Threonine Kinases - antagonists & inhibitors / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteins / Reagents / Schwann cells / Side effects / Signal Transduction - drug effects / Sodium / Synergistic effect / Transcription Factors - genetics / Transcription Factors - metabolism / Tumors / YAP-Signaling Proteins - genetics / YAP-Signaling Proteins - metabolism / Yes-associated protein