Crispr-mediated genome editing reveals a preponderance of non-oncogene addictions as targetable vulnerabilities in pleural mesothelioma.

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  • Additional Information
    • Source:
      Publisher: Elsevier Scientific Publishers Country of Publication: Ireland NLM ID: 8800805 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-8332 (Electronic) Linking ISSN: 01695002 NLM ISO Abbreviation: Lung Cancer Subsets: MEDLINE
    • Publication Information:
      Publication: Limerick : Elsevier Scientific Publishers
      Original Publication: Amsterdam, The Netherlands : Elsevier, c1985-
    • Subject Terms:
      Gene Editing* ; Pleural Neoplasms*/genetics ; Pleural Neoplasms*/drug therapy ; Pleural Neoplasms*/pathology ; CRISPR-Cas Systems* ; Mesothelioma*/genetics ; Mesothelioma*/pathology ; Mesothelioma*/drug therapy; Humans ; Cell Line, Tumor ; Animals ; Mice ; Gene Expression Regulation, Neoplastic ; Mesothelioma, Malignant/genetics ; Mesothelioma, Malignant/drug therapy ; Mesothelioma, Malignant/pathology ; Lung Neoplasms/genetics ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics
    • Abstract:
      Pleural mesothelioma (PM) is an aggressive cancer with limited treatment options. In particular, the frequent loss of tumor suppressors, a key oncogenic driver of the disease that is therapeutically intractable, has hampered the development of targeted cancer therapies. Here, we interrogate the PM genome using CRISPR-mediated gene editing to systematically uncover PM cell susceptibilities and provide an evidence-based rationale for targeted cancer drug discovery. This analysis has allowed us to identify with high confidence numerous known and novel gene dependencies that are surprisingly highly enriched for non-oncogenic pathways involved in response to various stress stimuli, in particular DNA damage and transcriptional dysregulation. By integrating genomic analysis with a series of in vitro and in vivo functional studies, we validate and prioritize several non-oncogene addictions conferred by CDK7, CHK1, HDAC3, RAD51, TPX2, and UBA1 as targetable vulnerabilities, revealing previously unappreciated aspects of PM biology. Our findings support the growing consensus that stress-responsive non-oncogenic signaling plays a key role in the initiation and progression of PM and provide a functional blueprint for the development of unprecedented targeted therapies to combat this formidable disease.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: CRISPR/Cas9; Genetic vulnerability; Non-oncogene addictions; Pleural mesothelioma (PM); Therapeutic targets
    • Publication Date:
      Date Created: 20241009 Date Completed: 20241110 Latest Revision: 20241110
    • Publication Date:
      20241114
    • Accession Number:
      10.1016/j.lungcan.2024.107986
    • Accession Number:
      39383772