美国麻省理工学院和哈佛大学布罗德研究所William R. Sellers团队近日取得一项新成果。经过不懈努力，他们发现条件特异性通路激活的系统分析可识别环境相关的合成致死。这一研究成果发表在2023年9月25日出版的国际学术期刊《自然-遗传学》上。

研究人员试图系统地识别特定基因激活诱导的癌症致死率。为此，研究人员开发了一种在500个条形码癌细胞系中同时获得功能遗传扰动的方法。使用这种方法，研究检测了激活十个关键通路节点时的泛癌脆弱性，揭示了与特定生物标志物相关的MAPK和PI3K通路选择性激活依赖。

特别是，研究人员在APC突变结直肠癌的亚群中发现了新的通路过度激活依赖性，其中通过敲低APC或直接过表达β-连环蛋白可进一步诱导WNT通路突变异种移植和患者来源类器官模型产生强大的抗肿瘤作用。总之，这项研究揭示了癌症中一类新的条件基因激活依赖性。

据了解，癌症靶向治疗的焦点主要集中在抑制癌症的关键途径上。相反，条件性激活信号通路作为筛选癌症脆弱性的新来源尚未得到深入表征。

附：英文原文

Title: Systematic profiling of conditional pathway activation identifies context-dependent synthetic lethalities

Author: Chang, Liang, Jung, Nancy Y., Atari, Adel, Rodriguez, Diego J., Kesar, Devishi, Song, Tian-Yu, Rees, Matthew G., Ronan, Melissa, Li, Ruitong, Ruiz, Paloma, Chaturantabut, Saireudee, Ito, Takahiro, van Tienen, Laurens M., Tseng, Yuen-Yi, Roth, Jennifer A., Sellers, William R.

Issue&Volume: 2023-09-25

Abstract: The paradigm of cancer-targeted therapies has focused largely on inhibition of critical pathways in cancer. Conversely, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been deeply characterized. In this study, we sought to systematically identify context-specific gene-activation-induced lethalities in cancer. To this end, we developed a method for gain-of-function genetic perturbations simultaneously across ~500 barcoded cancer cell lines. Using this approach, we queried the pan-cancer vulnerability landscape upon activating ten key pathway nodes, revealing selective activation dependencies of MAPK and PI3K pathways associated with specific biomarkers. Notably, we discovered new pathway hyperactivation dependencies in subsets of APC-mutant colorectal cancers where further activation of the WNT pathway by APC knockdown or direct β-catenin overexpression led to robust antitumor effects in xenograft and patient-derived organoid models. Together, this study reveals a new class of conditional gene-activation dependencies in cancer.

DOI: 10.1038/s41588-023-01515-7

Source: https://www.nature.com/articles/s41588-023-01515-7