利用CRISPR介导的基因编辑揭示胸膜间皮瘤的非致癌基因依赖性作为靶向弱点的优势

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

LUNG CANCER

影响因子:4.4

分区:医学2区 / 肿瘤学3区呼吸系统3区

发表日期:2024 Nov

作者: Duo Xu, Shun-Qing Liang, Min Su, Haitang Yang, Rémy Bruggmann, Simone Oberhaensli, Zhang Yang, Yanyun Gao, Thomas M Marti, Wenxiang Wang, Ralph A Schmid, Yongqian Shu, Patrick Dorn, Ren-Wang Peng

DOI: 10.1016/j.lungcan.2024.107986

摘要

胸膜间皮瘤（PM）是一种侵袭性极强的癌症，治疗选择有限。特别是，肿瘤抑制基因的频繁丧失，作为疾病的关键致癌驱动因素，难以通过治疗手段靶向，阻碍了靶向癌症疗法的发展。在本研究中，我们利用CRISPR基因编辑系统系统性地研究了PM基因组，旨在识别PM细胞的易感性，为靶向药物的发现提供循证依据。通过分析，我们高置信度地鉴定出许多已知及新颖的基因依赖性，这些依赖性在应对DNA损伤和转录失调等应激反应途径中高度富集，展现出非致癌通路的关键角色。结合基因组分析与体外及体内功能研究，我们验证并优先筛选出由CDK7、CHK1、HDAC3、RAD51、TPX2和UBA1赋予的非致癌性依赖性，揭示了PM生物学中未被充分认识的方面。我们的研究支持压力响应型非致癌信号在PM发生发展中的关键作用，并为开发前所未有的靶向治疗提供了功能性蓝图，旨在应对这一顽疾。

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.