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Article

Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma

1
Division of General Thoracic Surgery, Department of BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 50, CH3008 Bern, Switzerland
2
Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(8), 2310; https://doi.org/10.3390/cancers12082310
Received: 13 June 2020 / Revised: 1 August 2020 / Accepted: 4 August 2020 / Published: 17 August 2020
(This article belongs to the Special Issue Malignant Mesothelioma)
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’ 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. View Full-Text
Keywords: mesothelioma; tumor suppressor; targeted therapy; immunotherapy mesothelioma; tumor suppressor; targeted therapy; immunotherapy
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MDPI and ACS Style

Yang, H.; Xu, D.; Yang, Z.; Yao, F.; Zhao, H.; Schmid, R.A.; Peng, R.-W. Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma. Cancers 2020, 12, 2310. https://doi.org/10.3390/cancers12082310

AMA Style

Yang H, Xu D, Yang Z, Yao F, Zhao H, Schmid RA, Peng R-W. Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma. Cancers. 2020; 12(8):2310. https://doi.org/10.3390/cancers12082310

Chicago/Turabian Style

Yang, Haitang, Duo Xu, Zhang Yang, Feng Yao, Heng Zhao, Ralph A. Schmid, and Ren-Wang Peng. 2020. "Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma" Cancers 12, no. 8: 2310. https://doi.org/10.3390/cancers12082310

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