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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere0305121
Pages (from-to)e0305121
JournalPLoS ONE
Volume19
Issue number7 July
DOIs
StatePublished - Jul 31 2024

Keywords

  • Humans
  • Neurilemmoma/metabolism
  • p21-Activated Kinases/metabolism
  • Cell Proliferation/drug effects
  • Hippo Signaling Pathway
  • Neurofibromin 2/genetics
  • Signal Transduction/drug effects
  • Protein Serine-Threonine Kinases/metabolism
  • Cell Line, Tumor
  • Transcription Factors/metabolism
  • Apoptosis/drug effects
  • Drug Synergism
  • Neurofibromatosis 2/metabolism
  • YAP-Signaling Proteins/metabolism
  • Protein Kinase Inhibitors/pharmacology
  • Adaptor Proteins, Signal Transducing/metabolism
  • DNA-Binding Proteins/metabolism

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