CRISPR介导的基因组编辑揭示了非癌基因成瘾作为胸膜间皮瘤中的可靶向脆弱性
Crispr-mediated genome editing reveals a preponderance of non-oncogene addictions as targetable vulnerabilities in pleural mesothelioma
影响因子:4.40000
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
摘要
胸膜间皮瘤（PM）是一种侵略性癌症，治疗方案有限。特别是，经常抑制肿瘤的损失，这是该疾病的关键致癌驱动因素在治疗上棘手，这阻碍了靶向癌症疗法的发展。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，并为靶向癌症的发现提供了基于证据的基本原理。该分析使我们能够高度置信度识别许多已知和新颖的基因依赖性，这些基因依赖性令人惊讶地高度富集了涉及各种应激刺激的非核心途径，尤其是DNA损伤和转录失调。通过将基因组分析与一系列体外和体内功能研究相结合，我们验证和优先排序了由CDK7，CHK1，HDAC3，RAD51，TPX2和UBA1赋予的几种非顺体成瘾，并将其视为可靶向的脆弱性，揭示了先前未经认可的PM生物学方面。我们的发现支持了日益增长的共识，即应激反应性非康复信号传导在PM的启动和进展中起关键作用，并为开发前所未有的靶向疗法提供了功能性蓝图，以抗击这种富有良性的疾病。
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.