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

Autor: Razmik Ghukasyan, Keke Liang, Kevin Chau, Luyi Li, Charlotte Chan, Evan R. Abt, Thuc Le, Joon Y. Park, Nanping Wu, Alykhan Premji, Robert Damoiseaux, Tony Luu, Amanda Labora, Khalid Rashid, Jason M. Link, Caius G. Radu, Timothy R. Donahue
Rok vydání: 2023
Předmět:
Zdroj: Clinical Cancer Research.
ISSN: 1557-3265
1078-0432
DOI: 10.1158/1078-0432.ccr-22-3322
Popis: 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.
Databáze: OpenAIRE
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