{"doi":"10.1371/journal.pone.0305121","title":"Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma","abstract":"<jats:p>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 <jats:italic>in vivo</jats:italic>, 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.</jats:p>","journal":"PLOS ONE","year":2024,"id":668425,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":596132,"name":"Hoi Yee Chow","orcid":"0000-0002-4479-7598","position":1,"is_corresponding":false},{"id":711236,"name":"Sofiia Karchugina","orcid":"0000-0002-9648-8092","position":2,"is_corresponding":false},{"id":343747,"name":"Jonathan Chernoff","orcid":"0000-0002-4803-7836","position":3,"is_corresponding":false},{"id":1387607,"name":"Dorothy Benton","orcid":"0009-0006-5722-025X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma","abstract":"<jats:p>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 <jats:italic>in vivo</jats:italic>, 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.</jats:p>","is_dataset_classified":null,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39083549","pmcid":null,"openalex_id":"https://openalex.org/W4401166222","authors":[],"funders":[{"funder_name":"Children's Tumor Foundation","grant_id":"2121-05-001","title":null}],"total_grants":1,"fwci":1.6248,"citation_percentile":0.81630435,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":3},{"year":2026,"count":3}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1371/journal.pone.0305121","host_type":"journal"},{"url":"https://doi.org/10.1371/journal.pone.0305121","host_type":"publisher"},{"url":"https://dx.plos.org/10.1371/journal.pone.0305121","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39083549","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11290668","host_type":"repository"},{"url":"https://doaj.org/article/ea99a41025d443cbbb48ac461e1785c5","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11290668/pdf/pone.0305121.pdf","host_type":"repository"}],"fields_of_study":["Hippo pathway signaling and YAP/TAZ","Neurofibromatosis and Schwannoma Cases","Axon Guidance and Neuronal Signaling","Humans","Neurilemmoma","p21-Activated Kinases","Cell Proliferation","Hippo Signaling Pathway","Neurofibromin 2","Signal Transduction","Protein Serine-Threonine Kinases","Cell Line, Tumor","Transcription Factors","Apoptosis","Drug Synergism","Neurofibromatosis 2","YAP-Signaling Proteins","Protein Kinase Inhibitors","Adaptor Proteins, Signal Transducing","DNA-Binding Proteins"],"mesh_terms":["Hippo Signaling Pathway","YAP-Signaling Proteins","DNA-Binding Proteins","Drug Synergism","Humans","Neurilemmoma","Transcription Factors","Signal Transduction","Neurofibromatosis 2","Apoptosis","Protein Serine-Threonine Kinases","Neurofibromin 2","Cell Line, Tumor","Protein Kinase Inhibitors","Adaptor Proteins, Signal Transducing","Cell Proliferation","p21-Activated Kinases"],"keywords":["Merlin (protein)","Hippo signaling pathway","Neurofibromatosis type 2","Kinase","Cell biology","Cancer research","Biology","Cell growth","Actin cytoskeleton","Cell","Neurofibromatosis","Cytoskeleton","Genetics","Suppressor","Gene"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-14T11:12:43.466352Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}