Sting Agonist GSK3745417 Induces Apoptosis, Antiproliferation, and Cell Death in a Panel of Human AML Cell Lines and Patient Samples

GSK3745417 is currently in phase 1 development targeting solid tumor indications. Recent literature has suggested a role for STING (Stimulator of Interferon Genes) activation induced cytotoxicity in AML cells (Baba et al, Cell Death Dis, 2021; 12(4):322.), indicating potential for therapeutic benefit in AML/MDS.

To determine the implications of STING activation on tumor cells directly, GSK3745417 treatment was assessed in a screen against a panel of 93 tumor cell lines from various tumor origin. GSK3745417 treatment resulted in cytokine production across cell lines but cell growth inhibition in only 3 of the cell lines, including the only 2 AML cell lines in the panel. GSK3745417 was subsequently tested in an expanded panel of 13 AML cell lines. The data confirmed the cell growth inhibitory effect of GSK3745417 in 11/13 AML cell lines. Overall, growth inhibition was more potent than IFNβ induction, indicating a distinct growth inhibition/cytotoxicity mechanism in AML cells upon STING activation in addition to the potential to induce anti-AML immune response through type 1 IFN induction (Curran et al, Cell Rep, 2016;15(11):2357-66.).

Further study demonstrated caspase induction in 7 out of 11 responding cell lines upon GSK3745417 treatment which was blocked by apoptosis inhibitor QVD. This supports the hypothesis that GSK3745417 induced cytotoxicity in AML cells is driven through an apoptosis mechanism. GSK3745417 also blocked colony formation in primary AML samples from 5 donors.

GSK3745417 is able to induce growth inhibition with transient compound incubation in vitro in as little as 30 minutes to 1 hour. Taken together, this data suggests a role for GSK3745417 as a therapeutic in AML/MDS indications through dual mechanisms of direct tumor cell killing and immune activation at a clinically relevant dose.

The human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents under an IRB/EC approved protocol.

Schmidt:GSK: Current Employment, Other: Financial interest in GSK. Yang:Glaxo-Smith-Kline: Current Employment, Current holder of stock options in a privately-held company.