Co-inhibition of BET and NAE enhances BIM-dependent apoptosis with augmented cancer therapeutic efficacy.

ABSTRACT

Agents that inhibit bromodomain and extra-terminal domain (BET) proteins have been actively tested in the clinic as potential anticancer drugs. NEDD8-activating enzyme (NAE) inhibitors, represented by MLN4924, target the only activation enzyme in the neddylation pathway that has been identified as an attractive target for cancer therapy. In this study, we focus on the combination of BET inhibitors (BETis) and NAE inhibitors (NAEis) as a cancer therapeutic strategy and investigate its underlying mechanisms to explore and expand the application scope of both types of drugs. The results showed that this combination synergistically inhibited the proliferative activity of tumor cells from different tissues. Compared to a single drug, combination therapy had a weak effect on cycle arrest but significantly enhanced cell apoptosis. Furthermore, the growth of NCI-H1975 xenografts in nude mice was significantly inhibited by the combination without obvious body weight loss. Research on the synergistic mechanism demonstrated that combination therapy significantly increased the mRNA and protein levels of the proapoptotic gene BIM. The inhibition and knockout of BIM significantly attenuated the apoptosis induced by the combination, whereas the re-expression of BIM restored the synergistic effects, indicating that BIM induction plays a critical role in mediating the enhanced apoptosis induced by the co-inhibition of BET and NAE. Together, the enhanced transcription mediated by miR-17-92 cluster inhibition and reduced degradation promoted the increase in BIM levels, resulting in a synergistic effect. Collectively, these findings highlight the need for further clinical investigation into the combination of BETi and NAEi as a promising strategy for cancer therapy.