{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:07:54Z","timestamp":1760238474228,"version":"build-2065373602"},"reference-count":72,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,8,17]],"date-time":"2020-08-17T00:00:00Z","timestamp":1597622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004361","name":"Krebsliga Schweiz","doi-asserted-by":"publisher","award":["KFS-4851-08-2019"],"award-info":[{"award-number":["KFS-4851-08-2019"]}],"id":[{"id":"10.13039\/501100004361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["#310030_192648"],"award-info":[{"award-number":["#310030_192648"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Malignant pleural mesothelioma (MPM) is driven by the inactivation of tumor suppressor genes (TSGs). An unmet need in the field is the translation of the genomic landscape into effective TSG-specific therapies. Methods: We correlated genomes against transcriptomes of patients\u2019 MPM tumors, by weighted gene co-expression network analysis (WGCNA). The identified aberrant biochemical networks and potential drug targets induced by tumor suppressor loss were validated by integrative data analysis and functional interrogation. Results: CDKN2A\/2B loss activates G2\/M checkpoint and PI3K\/AKT, prioritizing a co-targeting strategy for CDKN2A\/2B-null MPM. CDKN2A deficiency significantly co-occurs with deletions of anti-viral type I interferon (IFN-I) genes and BAP1 mutations, that enriches the IFN-I signature, stratifying a unique subset, with deficient IFN-I, but proficient BAP1 for oncolytic viral immunotherapies. Aberrant p53 attenuates differentiation and SETD2 loss acquires the dependency on EGFRs, highlighting the potential of differentiation therapy and pan-EGFR inhibitors for these subpopulations, respectively. LATS2 deficiency is linked with dysregulated immunoregulation, suggesting a rationale for immune checkpoint blockade. Finally, multiple lines of evidence support Dasatinib as a promising therapeutic for LATS2-mutant MPM. Conclusions: Systematic identification of abnormal cellular processes and potential drug vulnerabilities specified by TSG alterations provide a framework for precision oncology in MPM.<\/jats:p>","DOI":"10.3390\/cancers12082310","type":"journal-article","created":{"date-parts":[[2020,8,17]],"date-time":"2020-08-17T06:33:20Z","timestamp":1597646000000},"page":"2310","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8732-5910","authenticated-orcid":false,"given":"Haitang","family":"Yang","sequence":"first","affiliation":[{"name":"Division of General Thoracic Surgery, Department of BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 50, CH3008 Bern, Switzerland"},{"name":"Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duo","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of General Thoracic Surgery, Department of BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 50, CH3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhang","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of General Thoracic Surgery, Department of BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 50, CH3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0699-079X","authenticated-orcid":false,"given":"Ralph A.","family":"Schmid","sequence":"additional","affiliation":[{"name":"Division of General Thoracic Surgery, Department of BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 50, CH3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren-Wang","family":"Peng","sequence":"additional","affiliation":[{"name":"Division of General Thoracic Surgery, Department of BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 50, CH3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.jtho.2018.06.011","article-title":"Scientific Advances and New Frontiers in Mesothelioma Therapeutics","volume":"13","author":"Mutti","year":"2018","journal-title":"J. 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