Combinatorial targeting of Hippo-STRIPAK and PARP elicits synthetic lethality in gastrointestinal cancers.
Combinatorial targeting of Hippo-STRIPAK and PARP elicits synthetic lethality in gastrointestinal cancers.
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Hippo-STRIPAK 和 PARP 的组合靶向可引发胃肠道癌症的合成致死率
DOI：
10.1172/jci155468
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发表时间：
2022-05-02
影响因子：
15.9
通讯作者：
Zhou, Zhaocai
中科院分区：
文献类型：
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作者：
An, Liwei;Cao, Zhifa;Nie, Pingping;Zhang, Hui;Tong, Zhenzhu;Chen, Fan;Tang, Yang;Han, Yi;Wang, Wenjia;Zhao, Zhangting;Zhao, Qingya;Yang, Yuqin;Xu, Yuanzhi;Fang, Gemin;Shi, Lei;Xu, Huixiong;Ma, Haiqing;Jiao, Shi;Zhou, Zhaocai
纹状体相互作用磷酸酶和激酶（STRIPAK）复合物整合导致细胞内活动的细胞外刺激。之前，我们发现STRIPAK是导致癌症中Hippo肿瘤抑制信号丢失的关键机制。在这里，我们确定了Hippo-STRIPAK复合物作为控制DNA双链断裂（DSB）修复和基因组稳定性的重要参与者。具体而言，我们发现哺乳动物STE 20样蛋白激酶1和2（MST 1/2），独立于经典的Hippo信号，直接磷酸化锌指MYND型8（ZMYND 8），因此导致细胞核中DNA修复的抑制。响应遗传毒性应激，IFN基因的环GMP-AMP合酶/刺激因子（cGAS/STING）途径被确定为经由TANK结合激酶1诱导的Hippo-STRIPAK的动态组装来传递核DNA损伤信号。（TBK 1诱导的）IKBKE 1-肌膜相关蛋白抑制因子的结构稳定因此，我们发现STRIPAK介导的MST 1/2失活增加了癌细胞的DSB修复能力，并赋予这些细胞对放射性和化学疗法以及聚（ADP-核糖）聚合酶（PARP）抑制的抗性。重要的是，在动物和患者来源的肿瘤模型中，用3种不同的肽抑制剂中的每一种靶向STRIPAK组装体有效地恢复了MST 1/2的激酶活性，以抑制DNA修复并使癌细胞对PARP抑制剂重新敏感。总体而言，我们的研究结果不仅揭示了我们认为是以前未被认识到的作用，STRIPAK在调节DSB修复，但也提供了翻译的意义，共同靶向STRIPAK和PARP的一种新型的合成致死性抗癌治疗。
The striatin-interacting phosphatase and kinase (STRIPAK) complexes integrate extracellular stimuli that result in intracellular activities. Previously, we discovered that STRIPAK is a key machinery responsible for loss of the Hippo tumor suppressor signal in cancer. Here, we identified the Hippo-STRIPAK complex as an essential player in the control of DNA double-stranded break (DSB) repair and genomic stability. Specifically, we found that the mammalian STE20-like protein kinases 1 and 2 (MST1/2), independent of classical Hippo signaling, directly phosphorylated zinc finger MYND type–containing 8 (ZMYND8) and hence resulted in the suppression of DNA repair in the nucleus. In response to genotoxic stress, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway was determined to relay nuclear DNA damage signals to the dynamic assembly of Hippo-STRIPAK via TANK-binding kinase 1–induced (TBK1-induced) structural stabilization of the suppressor of IKBKE 1– sarcolemma membrane–associated protein (SIKE1-SLMAP) arm. As such, we found that STRIPAK-mediated MST1/2 inactivation increased the DSB repair capacity of cancer cells and endowed these cells with resistance to radio- and chemotherapy and poly(ADP-ribose)polymerase (PARP) inhibition. Importantly, targeting the STRIPAK assembly with each of 3 distinct peptide inhibitors efficiently recovered the kinase activity of MST1/2 to suppress DNA repair and resensitize cancer cells to PARP inhibitors in both animal- and patient-derived tumor models. Overall, our findings not only uncover what we believe to be a previously unrecognized role for STRIPAK in modulating DSB repair but also provide translational implications of cotargeting STRIPAK and PARP for a new type of synthetic lethality anticancer therapy.