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 8

Rational restoration of Hippo kinase activity resensitizes tumors to PARP inhibition.

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Rational restoration of Hippo kinase activity resensitizes tumors to PAR...
(A) Western blot analysis of p-MST1/2 and ZMYND8 across 11 GC cell lines. (B) IC50 values measured from the GC cell lines after they were treated with each PARPi. A group was defined to be sensitive or resistant to PARPi based on whether the IC50 was, respectively, less than or greater than 20 μM. (C) Linear regression analysis of PARPi sensitivity and Hippo kinase activity across the GC cells. (D) Plot showing a dose-dependent suppression of HR repair by SHAP (n = 3). (E) Plots showing that treatment of GC cells with SHAP resensitized the cells to PARPi. Specifically, BGC-823 and AGS cells were each treated with various doses of rucaparib in the presence of 0, 0.5, and 2.0 μM SHAP for 24 hours. (F and G) Results showing that SHAP treatment dramatically enhanced rucaparib-mediated antitumor efficiency in vivo. Nude mice bearing GC tumors were intraperitoneally administered SHAP and rucaparib, either alone or in combination. (F) Tumor size was measured every 3 days, and (G) tumors were photographed and weighed on day 18 (n = 4 mice/group). **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Dunnett’s post hoc test (D and G ) and unpaired Student’s t test (F). See also Supplemental Figure 9.