MEK inhibition sensitizes pancreatic cancer to STING agonism by tumor-cell intrinsic amplification of type I interferon signaling

by Selleckchem | Aug 28 2023

Purpose: STING (Stimulator of Interferon Genes) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor-cell intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity.

Experimental design: We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo.

Results: We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce Type I interferon-dependent cell death in vitro and tumor regression in vivo. We parsed NF-κB-dependent and independent mechanisms that mediate STING-driven Type I interferon production and show that MEK signaling inhibits this effect by suppressing NF-κB activation.

Conclusions: Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity, and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.

Comments:

That's an interesting study! It appears that the researchers aimed to investigate the potential of combining STING agonists with other therapies to improve their effectiveness in treating solid tumors, specifically pancreatic ductal adenocarcinoma (PDAC). They screened a large number of kinase inhibitors to identify compounds that could enhance the tumor-cell intrinsic effects of a specific STING agonist called diABZI.

The results of their study showed that MEK inhibitors exhibited the greatest synergy with diABZI. MEK inhibition enhanced the ability of STING agonism to induce cell death through Type I interferon-dependent mechanisms in vitro and tumor regression in vivo. It was also observed that this synergy was most significant in cells with high expression of STING.

The researchers further investigated the underlying mechanisms of this synergy and found that MEK signaling inhibited the NF-κB pathway, which is involved in STING-driven Type I interferon production. By suppressing NF-κB activation, MEK inhibitors enhanced the cytotoxic effects of STING agonism on PDAC cells, independent of tumor immunity.

Overall, this study suggests that combining STING agonists with MEK inhibitors can potentiate the therapeutic benefits of STING agonism in PDAC by promoting tumor cell death through Type I interferon-dependent mechanisms. These findings contribute to the understanding of the molecular interactions and potential combination therapies that could be explored to improve the efficacy of STING agonists in the treatment of solid tumors.