Combinatorial targeting of Hippo-STRIPAK and PARP elicits synthetic lethality in gastrointestinal cancers
Liwei An, … , Shi Jiao, Zhaocai Zhou
Liwei An, … , Shi Jiao, Zhaocai Zhou
Published March 15, 2022
Citation Information: J Clin Invest. 2022;132(9):e155468. https://doi.org/10.1172/JCI155468.
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Research Article Cell biology Gastroenterology

Combinatorial targeting of Hippo-STRIPAK and PARP elicits synthetic lethality in gastrointestinal cancers

Abstract

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.

Authors

Liwei An, Zhifa Cao, Pingping Nie, Hui Zhang, Zhenzhu Tong, Fan Chen, Yang Tang, Yi Han, Wenjia Wang, Zhangting Zhao, Qingya Zhao, Yuqin Yang, Yuanzhi Xu, Gemin Fang, Lei Shi, Huixiong Xu, Haiqing Ma, Shi Jiao, Zhaocai Zhou

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Figure 1

The Hippo-containing STRIPAK complex is essential for DSB repair.

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The Hippo-containing STRIPAK complex is essential for DSB repair. (A) Sc...
(A) Schematic illustration of the miniscreen of STRIPAK in DSB repair. (B) Plot showing the regulation of HR repair by the siRNA-mediated knockdown components of STRIPAK (n = 3). (C) Images showing the results of the indicated HGC-27 cells exposed to IR (10 Gy) and collected 0.5 and 4 hours after treatment before being subjected to a neutral comet assay (scale bar: 50 μm), and a plot providing quantifications of the tail moment at 4 hours (n = 30 cells/group). (D) Schematic presentation of the assembly of the STRIPAK-MST1/2 complex and SIKE1 mutants (M1 and M2). (E) Images and plot showing that SIKE1 promoted genomic stability within STRIPAK. HGC-27 cells (WT and its derivatives) were first treated with etoposide for 1 hour before being subjected to the sphere formation assay. Scale bar: 60 μm. (F) Plot showing that MST1/2 limited cancer cell sphere formation in a manner dependent on their kinase activity of MST1/2. HGC-27 cells (WT and its derivatives) were treated and processed as in E. (G) Gels showing that SHAP treatment attenuated DNA repair capacity. HGC-27 cells pretreated with etoposide for 1 hour were further incubated with or without SHAP peptides. **P < 0.01 and ***P < 0.001, by 1-way ANOVA with Dunnett’s post hoc test, compared with control (B and C) and unpaired Student t test (E and F). See also Supplemental Figures 1 and 2. Ctrl, control.