Birinapant is a Smac-mimetic (SM) evaluated in phase 2 trials for the treatment of cancer. SMs antagonize Inhibitor of APoptosis (IAP) proteins and simultaneously induce TNF secretion to render cancers sensitive to TNF induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM treated cells. We show that p38 inhibitors increased TNF induced by SM. Unexpectedly, and even though p38 is required for Toll-Like Receptors to induce TNF, loss of p38 or the downstream kinase MK2 increased induction of TNF by SM. Hence, we show that p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus.

The p38/MK2 pathway widely acknowledged to be required for production of the inflammatory cytokine, TNF. This fact led to a concerted effort by many pharmaceutical companies to develop p38 inhibitors as anti-inflammatory drugs. Although many of the drugs were relatively tolerated by patients, they did not perform adequately as anti-inflammatory drugs in clinical trials.

The combination of birinapant and p38 inhibitors was however well-tolerated in vivo by mice and proved an effective combination treatment for primary AML compared to either drug alone. Our preclinical study therefore provides a rationale for repurposing p38 or MK2 inhibitors to treat cancers.