{"doi":"10.1101/2025.02.18.638668","title":"A genetic signature predicts aggressive paraganglioma sensitivity to dual PI3K-CDK4/6 inhibition therapy","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Effective medical therapies for metastatic paraganglioma (mPPGL) are currently lacking, leading to dismal prognosis. Building on our knowledge of molecular mechanisms driving PPGL progression, we assessed the therapeutic potential of targeting two critical processes: PI3K signaling and cell cycle regulation. The efficacy of buparlisib (PI3Ki) and ribociclib (CDK4/6i), individually and combined, was assessed\n                  <jats:italic>in vitro</jats:italic>\n                  using PPGL cell lines, rat– and patient-derived primary cells, and\n                  <jats:italic>in vivo</jats:italic>\n                  using PPGL cells-derived mouse xenografts. The combination therapy demonstrated superior antitumor activity compared to single agents, particularly\n                  <jats:italic>in vivo</jats:italic>\n                  . Mechanistically, the efficacy of the combination therapy was associated to the downregulation of FOXM1-controlled genes implicated in mitotic spindle assembly and chromosomal segregation, leading to mitotic catastrophe. Data mining and qRT-PCR showed this genetic signature to be upregulated in human mPPGLs. This suggests that aggressive PPGLs exhibit heightened vulnerability to dual PI3K and CDK4/6 inhibition, offering a promising therapeutic avenue for these challenging cancers.\n                </jats:p>","journal":null,"year":null,"id":646004,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"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":1682347,"name":"Federica Gentile","orcid":null,"position":1,"is_corresponding":false},{"id":1682348,"name":"Sebastian Gulde","orcid":null,"position":2,"is_corresponding":false},{"id":1018689,"name":"Daniela De Martino","orcid":"0000-0001-7713-5876","position":3,"is_corresponding":false},{"id":1275384,"name":"Julian Maurer","orcid":null,"position":4,"is_corresponding":false},{"id":1682349,"name":"Katyayni Ganesan","orcid":null,"position":5,"is_corresponding":false},{"id":860508,"name":"Katharina Wang","orcid":"0000-0002-7795-1395","position":6,"is_corresponding":false},{"id":184024,"name":"Nicole Bechmann","orcid":null,"position":7,"is_corresponding":false},{"id":462168,"name":"Elena Rapizzi","orcid":"0000-0002-3826-2714","position":8,"is_corresponding":false},{"id":230213,"name":"Mercedes Robledo","orcid":"0000-0001-6256-5902","position":9,"is_corresponding":false},{"id":1682350,"name":"Ester Arroba","orcid":null,"position":10,"is_corresponding":false},{"id":658313,"name":"Stephan Herzig","orcid":"0000-0003-3950-3652","position":11,"is_corresponding":false},{"id":860510,"name":"Svenja Nölting","orcid":"0000-0002-7064-590X","position":12,"is_corresponding":false},{"id":1220742,"name":"Hermine Mohr","orcid":"0000-0002-3061-1166","position":13,"is_corresponding":false},{"id":1220745,"name":"Natalia S. Pellegata","orcid":"0000-0002-8000-7784","position":14,"is_corresponding":false},{"id":1682346,"name":"Bhargavi Karna","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"A genetic signature predicts aggressive paraganglioma sensitivity to dual PI3K-CDK4/6 inhibition therapy","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Effective medical therapies for metastatic paraganglioma (mPPGL) are currently lacking, leading to dismal prognosis. Building on our knowledge of molecular mechanisms driving PPGL progression, we assessed the therapeutic potential of targeting two critical processes: PI3K signaling and cell cycle regulation. The efficacy of buparlisib (PI3Ki) and ribociclib (CDK4/6i), individually and combined, was assessed\n                  <jats:italic>in vitro</jats:italic>\n                  using PPGL cell lines, rat– and patient-derived primary cells, and\n                  <jats:italic>in vivo</jats:italic>\n                  using PPGL cells-derived mouse xenografts. The combination therapy demonstrated superior antitumor activity compared to single agents, particularly\n                  <jats:italic>in vivo</jats:italic>\n                  . Mechanistically, the efficacy of the combination therapy was associated to the downregulation of FOXM1-controlled genes implicated in mitotic spindle assembly and chromosomal segregation, leading to mitotic catastrophe. Data mining and qRT-PCR showed this genetic signature to be upregulated in human mPPGLs. This suggests that aggressive PPGLs exhibit heightened vulnerability to dual PI3K and CDK4/6 inhibition, offering a promising therapeutic avenue for these challenging cancers.\n                </jats:p>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19767382","pmcid":null,"openalex_id":"https://openalex.org/W4407864340","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2025,"count":1}],"oa_status":"green","license":"https://www.biorxiv.org/about/FAQ#license","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/02/23/2025.02.18.638668.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/02/23/2025.02.18.638668.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2025.02.18.638668","host_type":"publisher"},{"url":"https://doi.org/10.1101/2025.02.18.638668","host_type":"repository"}],"fields_of_study":["Adrenal and Paraganglionic Tumors","Pituitary Gland Disorders and Treatments","Hormonal Regulation and Hypertension"],"mesh_terms":[],"keywords":["Paraganglioma","Signature (topology)","Sensitivity (control systems)","Dual (grammatical number)","Oncology","Medicine","Internal medicine","Pathology","Mathematics","Art","Engineering"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T11:04:15.795642Z","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":[]}