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 9

Cotargeting of STRIPAK and PARP elicits synthetic lethality in tumor cells.

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Cotargeting of STRIPAK and PARP elicits synthetic lethality in tumor cel...
(A) Schematic illustration of the STRIPAK assembly peptide inhibitors SAIP-1 and SAIP-2. (B) Gels showing that inclusion of SAIP-1 and SAIP-2 each restored Hippo kinase activity in BGC-823 cells. (C) Plots showing that SAIP1/2 in combination with PARPi resulted in synthetic lethality in BGC-823 cancer cells (n = 3). (D) Photograph showing that SAIP-1/2 synergistically augmented rucaparib-mediated antitumor efficiency in vivo (n = 3 mice/group in 1 experiment; n = 2 assays). Dot plot represents mouse tumor weights from 2 experiments (n = 6 mice per group) in each group. (E) Plots showing that SAIP-1/2 had a synthetic lethality effect with PARPi in gastric PDCs with low Hippo activity (n = 3). (F and G) Gels and plots showing that SAIP-1/2 had a synthetic lethality effect with PARPi in colon PDCs with low Hippo activity. (F) Western blot analysis of p-MST1/2 levels in 4 colon cancer PDC lines. (G) PDC35 cells were further treated with various doses of olaparib or rucaparib in the presence of 0, 2.5, and 5.0 μM SAIP-1 (left panel) or SAIP-2 (right panel) for 24 hours before cell viability analysis. CC, colon cancer. ***P < 0.001, by 1-way ANOVA with Dunnett’s post hoc test (C, D, and E). See also Supplemental Figure 10.