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 to result in intracellular activities. Previously, we discovered STRIPAK to be a key machinery responsible for loss of the Hippo tumor suppressor signal in cancer. Here, we identified the Hippo-STRIPAK complex to be an essential player for the control of DNA double-strand break (DSB) repair and genomic stability. Specifically, the MST1/2 kinases were found, independent of the classical Hippo signaling, to directly phosphorylate ZMYND8 and hence result in suppression of DNA repair in the nucleus. In response to genotoxic stress, the cGAS-STING pathway was determined to relay nuclear DNA damage signals to the dynamic assembly of Hippo-STRIPAK via a TBK1-induced structural stabilization of the SIKE1-SLMAP arm. As such, STRIPAK-mediated MST1/2 inactivation was found to increase the DSB repair capacity of cancer cells and to endow these cells with resistance to radio/chemotherapy and PARP inhibition. Importantly, targeting the STRIPAK assembly with each of three distinct peptide inhibitors efficiently recovered the kinase activity of MST1/2 to suppress DNA repair and re-sensitize cancer cells to PARPi in both animal and patientderived tumor models. Overall, our findings not only uncovered a previously unrecognized role for STRIPAK in modulating DSB repair, but also provided translational implications of co-targeting STRIPAK and PARP for a new type of synthetic lethality anti-cancer therapy.

Targeting the cGAS‐STING Pathway Inhibits Peripheral T‐cell Lymphoma Progression and Enhances the Chemotherapeutic Efficacy

“…Under genotoxic stress, the cGAS‐STING pathway transmits nuclear DNA damage signals to the dynamic assembly of Hippo‐striatin‐interacting phosphatase and kinase (STRIPAK) via TBK1; subsequently, Hippo kinase is inactivated by STRIPAK, thereby increasing the DNA repair capacity of cancer cells and endowing these cells with chemotherapy resistance. [ 45 ] In esophageal carcinoma, the Janus kinase‐2/STAT3 pathway, downstream of the cGAS‐STING pathway, is phosphorylated, enhancing the arrest of cell cycle‐mediated DNA repair and antagonizing the radiation‐induced killing effect. [ 46 ] DOX‐induced cytoplasmic release of mitochondrial DNA activates the cGAS‐STING‐TBK1 pathway, triggering the expression of specific clusters of IFN‐stimulated genes, including poly (ADP‐ribose) polymerase 9.…”

The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

“…1 The type I interferon-mediated STING pathway is also an important pathway influencing SL. 181 Novel dual PARP and HDAC inhibitors induce BRCAness in TNBC to restore SL, activate tumor IFN signaling, induce cytokine production through the cGAS-STING pathway and enhance immune responses. 182 Furthermore, NF-κB, IL-6, eIF2α, and YAP1-LOX/β1 integrin-SPP1 are being investigated as SL therapies for tumors.…”

“…In addition, interferon‐α (IFNα) could further enhance olaparib‐induced apoptosis and inhibition of cell activity 1 . The type I interferon‐mediated STING pathway is also an important pathway influencing SL 181 . Novel dual PARP and HDAC inhibitors induce BRCAness in TNBC to restore SL, activate tumor IFN signaling, induce cytokine production through the cGAS‐STING pathway and enhance immune responses 182 .…”

Cellular Impacts of Striatins and the STRIPAK Complex and Their Roles in the Development and Metastasis in Clinical Cancers (Review)

“…As key machinery involved in the loss of the tumour-suppressive Hippo signalling pathway, STRIPAK complex-mediated MST1/2 inactivation of Hippo has been shown to facilitate DNA double-stranded break (DSB), inducing resistance to drug therapies [ 80 ]. Interestingly, although STRIP1 depletion has a tumour-suppressive role in breast cancer proliferation via communication with P21 and P27, it showed a contradictory characteristic upon the administration of chemotherapies to cells [ 39 ].…”

“…Although a lower level of STRIP1 was shown to supress breast cancer cell proliferation via interference with cell cycle regulation, decreased STRIP1 exhibited tumour-promoting effects when cells were treated with a non-lethal dose of doxorubicin or cisplatin [ 39 ]. STRIPAK-mediated deactivating of MST1/2 in Hippo signalling also endows cells with resistance to chemo-, radiotherapies, and PARPi (poly ADP ribose polymerase inhibitor), an inhibitor to modulate DNA repair [ 80 ]. Furthermore, silencing of STRN4 was shown to sensitise pancreatic cancer cells to gemcitabine [ 86 ].…”