The Role of Pathogenic Mimicry Response Leading to Mitochondrial Dysfunction in Ovarian Cancer

Abstract

Approximately 10-15% of epithelial ovarian cancer (EOC) patients that have BRCA mutations and homologous recombination deficiency (HRD) are successfully treated with FDA-approved poly (ADP-ribose) polymerase (PARP) inhibitors resulting in synthetic lethality and antitumor responses. While some patients with BRCA-wildtype EOC have shown a response to single agent PARP inhibitor (PARPi) therapy, the majority do not respond. This suggests the need for the development of novel combination therapies for EOC. DNA methyltransferase inhibitors (DNMTis) activate transcriptionally silenced genes and repeat sequences, including endogenous retroviruses (ERVs), that increase dsRNA in the cytosol, leading to interferon (IFN) signaling and antitumor immune responses, in a mechanism known as viral mimicry. Combining PARPi with DNA methyltransferase inhibitors (DNMTis) have been shown to not only induce synergistic cytotoxicity in multiple cancers, including EOC with wildtype BRCA, but also increase both cytosolic dsDNA dsRNA, leading to STING-mediated interferon (IFN) and inflammasome (NFKB-TNFα) signaling, resulting in generation of HRD. Recent research shows that mitochondria (mt) are a gateway to IFN/inflammasome signaling and that release of mtDNA into the cytosol can activate innate immune signaling pathways, including STING. Importantly, recent reports suggest that the little studied ds RNA/DNA sensor ZNFX1, through interaction with mt proteins, is an important regulator of the IFN response in viral infection. Here, I show that in EOC, DNMTis and PARPi treatment increases expression of ZNFX1 and colocalization with mitochondrial antiviral protein MAVs in the mt outer membrane. This combination drug treatment also induces mt reactive oxygen species (ROS) and fragmented mtDNA release into the cytosol, resulting in STING-dependent inflammasome signaling. ZNFX1 knockout attenuates these dynamics, thus defining ZNFX1 as essential for interferon /inflammasome signaling induced by mtDNA damage. Overall, we suggest that ZNFX1 represents a novel master regulator of mt-mediated STING-dependent IFN and inflammasome signaling in OC and other solid malignancies.