MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer.

IF 29.7 1区 医学 Q1 ONCOLOGY Cancer discovery Pub Date : 2024-07-26 DOI:10.1158/2159-8290.CD-23-1529
Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Toyoki Yoshimoto, Aktan Alpsoy, Maria C Panepinto, Francesca Minicozzi, Joseph R Merrill, Amanda M Cafiero, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E Demerdash, Tse-Luen Wee, David L Spector, Scott K Lyons, David A Tuveson, Paolo Cifani, Christopher R Vakoc
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Abstract

The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.

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在人类癌症中,MARK2/MARK3 激酶是 YAP/TAZ 的催化共依赖因子。
在人类癌症中,Hippo 信号通路普遍失调,导致肿瘤对 YAP/TAZ 转录辅激活因子产生强大的依赖性。在这里,我们利用旁系共同靶向 CRISPR 筛选确定了激酶 MARK2/3 是 YAP/TAZ 在各种癌症和肉瘤中发挥功能的绝对催化条件。这一观察结果的基础是 MARK2/3 对 NF2 和 YAP/TAZ 的直接磷酸化,它能有效逆转 Hippo 模块激酶 LATS1/2 的肿瘤抑制活性。为了模拟MARK2/3的靶向作用,我们将幽门螺杆菌中的CagA蛋白作为MARK2/3的催化抑制剂,结果表明它能使体内已形成的肿瘤消退。这些发现共同揭示了MARK2/3在人类癌症中与YAP/TAZ的强大协同依赖关系;这些靶点可能是恢复Hippo通路介导的肿瘤抑制的药理学靶点。
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来源期刊
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
期刊介绍: Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.
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