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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Combinatorial targeting of Hippo-STRIPAK and PARP elicits synthetic lethality in gastrointestinal cancers
Liwei An1, Zhifa Cao2, Pingping Nie2
1Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai, China.
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.
Insights
The Hippo-STRIPAK complex regulates DNA repair and genomic stability. Inhibiting STRIPAK resensitizes cancer cells to therapies like PARP inhibitors, offering a new synthetic lethality approach.
Area of Science:
- Cell Biology
- Molecular Oncology
- DNA Repair Mechanisms
Background:
- Striatin-interacting phosphatase and kinase (STRIPAK) complexes integrate extracellular signals.
- STRIPAK was previously identified as crucial for Hippo tumor suppressor pathway loss in cancer.
- Genomic instability is a hallmark of cancer, driven by impaired DNA repair.
Purpose of the Study:
- To investigate the role of the Hippo-STRIPAK complex in DNA double-stranded break (DSB) repair and genomic stability.
- To elucidate the molecular mechanisms by which STRIPAK influences DNA repair.
- To explore the therapeutic potential of targeting STRIPAK in cancer treatment.
Main Methods:
- Investigated the phosphorylation of ZMYND8 by MST1/2 in response to genotoxic stress.
- Utilized the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway to understand DNA damage signaling.
- Employed peptide inhibitors to target STRIPAK assembly in cellular and animal models.
- Assessed cancer cell resistance and resensitization to radio-, chemo-, and PARP inhibition therapies.
Main Results:
- The Hippo-STRIPAK complex directly regulates DNA DSB repair and maintains genomic stability.
- Mammalian STE20-like protein kinases 1 and 2 (MST1/2), independent of classical Hippo signaling, phosphorylate ZMYND8, suppressing nuclear DNA repair.
- The cGAS/STING pathway relays DNA damage signals to STRIPAK assembly via TBK1-induced stabilization of the SIKE1-SLMAP arm.
- STRIPAK-mediated MST1/2 inactivation enhances cancer cell DSB repair, conferring resistance to various therapies, including PARP inhibition.
- Peptide inhibitors targeting STRIPAK assembly restored MST1/2 activity, suppressed DNA repair, and resensitized cancer cells to PARP inhibitors in preclinical models.
Conclusions:
- STRIPAK plays a previously unrecognized role in modulating DNA DSB repair.
- Targeting STRIPAK assembly presents a novel therapeutic strategy for enhancing cancer treatment efficacy.
- Co-targeting STRIPAK and PARP inhibitors offers a promising synthetic lethality approach for a new class of anticancer therapy.
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