The loss of p38 or MK2 enhances SMAC-mimetic–mediated TNF production and cytotoxicity.

  • Major finding: The loss of p38 or MK2 enhances SMAC-mimetic–mediated TNF production and cytotoxicity.

  • Mechanism: The p38/MK2 pathway inhibits SMAC-mimetic–driven phosphorylation of JNK1/2 and ERK1/2.

  • Impact: p38 or MK2 inhibitors may increase the clinical antitumor efficacy of SMAC-mimetics.

SMAC (encoded by DIABLO)-mimetics (SM) are a class of small-molecule compounds that triggers the proteasomal degradation of inhibitors of apoptosis (IAP) and promotes the secretion of the cytokine tumor necrosis factor (TNF). In the absence of IAPs, TNF fails to completely activate canonical NFκB signaling, resulting in TNF-induced cell death. To elucidate the mechanism underlying the induction of TNF production by SMs, Lalaoui and colleagues screened SM-treated cells with a panel of kinase inhibitors to identify compounds that enhanced TNF production. Of the 134 kinase inhibitors tested, inhibitors that target the MAPK p38 exhibited the greatest potency in enhancing SM-induced TNF production in bone marrow–derived macrophages (BMDM). This result was very surprising because normally following an inflammatory stimulus, such as toll-like receptor activation, p38 phosphorylates MAPKAP kinase 2 (MK2, encoded by MAPKAPK2) to increase TNF expression. Consistent with these findings, however, BMDMs from p38−/− or MAPKAPK2−/− mice treated with the SM CompA exhibited increased TNF expression and TNF production compared with BMDMs from wild-type mice treated with CompA. Mechanistically, the p38/MK2 pathway inhibited SM-induced phosphorylation of c-jun-NH2 kinase (JNK) 1/2 and ERK1/2, which resulted in decreased TNF production. Inhibition of the p38/MK2 pathway significantly enhanced SM-induced TNF production and apoptotic cell death, both of which could be prevented with Necrostatin, a receptor-interacting serine-threonine kinase 1 (RIPK1) inhibitor in BMDMs. Similarly, combination treatment of an MK2 inhibitor or a clinical p38 inhibitor and birinapant, an SM currently in clinical trial, induced greater TNF production and RIPK1-dependent cell death than birinapant treatment alone in transgenic murine acute myelogenous leukemia (AML) models and AML samples from patients. Taken together, these findings suggest that inhibition of the p38/MK2 pathway heightens SM-mediated cytotoxicity against AML and provide a rationale for clinically developing the combination of clinical p38 inhibitors and SMs, both of which are well tolerated, for hematologic cancers.

Lalaoui N, Hanggi K, Brumatti G, Chau D, Nguyen N-YN, Vasilikos L, et al. Targeting p38 or MK2 enhances the anti-leukemic activity of smac-mimetics. Cancer Cell 2016;29:145–58.