An investigation of the engagement of cGAS STING signaling upon DNA damage in cancer cells

Abstract

DNA damage is a common in feature of cancer cells, potentially causing nuclear and mitochondrial DNA to leak into the cytoplasm through various mechanisms. Accumulation of cytoplasmic DNA can lead to the engagement of the cGAS-STING pathway, which in turn modulates the immune response in the tumor microenvironment. While STING signaling has been shown to have anti-cancer activity through interferon-β production, recent evidence suggests that it may also drive the secretion of proinflammatory and pro-tumorigenic factors, particularly in the context of the DNA damage response to radio and chemotherapies. In this PhD project, we found that pharmacological inhibition of the cGAS-STING pathway can reduce the production of pro-tumorigenic IL-6, in select cancer cells. However, some cancer cells that rely on non-canonical STING signaling were resistant to this inhibition. Interestingly, we also discovered that STING inhibition could result in enhanced cancer cell growth, which we attributed to a decreased basal interferon activity in these cells. To limit the production of pro-inflammatory factors upon DNA damage while retaining the antiproliferative effects of the STING-interferon axis, we investigated the inhibition of downstream modulators of NF-κB signaling, such as ERK1/2. Additionally, we discovered that a novel STING-TBK1 inhibitor, IDX, modulated both canonical and non-canonical STING signaling. Our further analyses indicated that the inhibitory activity of IDX on non-canonical STING driven NF-κB signaling was independent of ERK1/2 MAP kinases. We also found that an inhibition of cGAMP extracellular secretion through inhibition of VRAC-LRRC8A, significantly reduced the amplification of DNA-damage driven inflammation mediated by cGAS-STING in cancer tissues. These findings suggest that strategies that limit the diffusion of cGAMP may help reduce the production of pro-tumorigenic pro-inflammatory factors during chemo and radiotherapies. Collectively, the works from this PhD have shed light on the complex role of the cGAS-STING pathway in cancer and have highlighted novel potential strategies for improving the efficacy of cancer radio and chemotherapies through the modulation of this pathway.