胸膜间皮瘤 (PM) 是一种侵袭性癌症，治疗选择有限。特别是，肿瘤抑制因子的频繁丢失阻碍了靶向癌症疗法的发展，肿瘤抑制因子是治疗上难以治愈的疾病的关键致癌驱动因素。在这里，我们使用 CRISPR 介导的基因编辑来询问 PM 基因组，以系统地揭示 PM 细胞的敏感性，并为靶向癌症药物的发现提供基于证据的基本原理。这项分析使我们能够高度可信地识别出许多已知和新颖的基因依赖关系，这些依赖关系令人惊讶地高度丰富，涉及响应各种应激刺激（特别是 DNA 损伤和转录失调）的非致癌途径。通过将基因组分析与一系列体外和体内功能研究相结合，我们验证并优先考虑了 CDK7、CHK1、HDAC3、RAD51、TPX2 和 UBA1 赋予的几种非癌基因成瘾作为可靶向的漏洞，揭示了 PM 生物学以前未被重视的方面。我们的研究结果支持了越来越多的共识，即应激反应性非致癌信号在 PM 的发生和进展中发挥着关键作用，并为开发前所未有的靶向疗法来对抗这种可怕的疾病提供了功能蓝图。版权所有 © 2024 ）。由 Elsevier B.V. 出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.