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MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell-intrinsic Amplification of Type I IFN
Razmik Ghukasyan1,2, Keke Liang1,3, Kevin Chau4
1Department of Surgery, University of California Los Angeles, Los Angeles, California.
Purpose:
Stimulator of interferon genes (STING) 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 IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB 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.
Insights
MEK inhibitors synergize with STING agonists to enhance tumor cell death in pancreatic cancer. This combination therapy boosts STING agonist potency for improved treatment outcomes.
Area of Science:
- Immunology and Cancer Therapy
- Molecular and Cellular Oncology
Background:
- Stimulator of interferon genes (STING) agonists show promise for solid tumors like pancreatic ductal adenocarcinoma (PDAC).
- Current STING agonist monotherapies yield modest response rates, necessitating combination strategies for enhanced efficacy.
Purpose of the Study:
- To identify combination therapies that augment the tumor cell-intrinsic effects of STING agonists.
- To elucidate mechanisms of synergy between STING agonism and other agents, independent of tumor immunity.
Main Methods:
- Screened 430 kinase inhibitors for synergistic effects with the STING agonist diABZI on tumor cell death.
- Investigated mechanisms of synergy driving tumor cell death in vitro and tumor regression in vivo.
- Analyzed the role of MEK signaling in STING-mediated type I interferon production and NFκB activation.
Main Results:
- MEK inhibitors demonstrated significant synergy with diABZI, particularly in high STING-expressing cells.
- MEK inhibition amplified STING agonist-induced type I interferon-dependent cell death and tumor regression.
- MEK signaling was found to suppress NFκB activation, thereby inhibiting STING-driven type I interferon production.
Conclusions:
- STING agonism exhibits direct cytotoxic effects on PDAC cells, independent of immune modulation.
- Combination therapy with MEK inhibitors synergistically enhances the therapeutic benefits of STING agonists.
- Targeting MEK signaling represents a viable strategy to potentiate STING-based cancer treatments.
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