BRD4 inhibition promotes TRAIL-induced apoptosis by suppressing the transcriptional activity of NF-κB in NSCLC.

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) can induce apoptosis preferentially in tumor cells while causing virtually no damage to normal cells. However, their therapeutic potential is limited by occurring resistance in tumor cells, including non-small cell lung cancer (NSCLC). Thus, elucidation of the molecular targets and signaling pathways responsible for TRAIL resistance is imperative for devising effective therapeutic strategies for TRAIL resistant cancers. In the present study, we demonstrated that inhibition of Bromodomain-containing protein 4 (BRD4) or genetic knock-down of BRD4, an epigenetic reader and master transcription coactivator, can sensitize lung cancer cells to TRAIL. This sensitization is in a caspase-dependent manner. Inhibition of BRD4 by small molecule inhibitor (+)-JQ-1 and genetic knock-down of BRD4 can both recruit the FADD and activate caspases. The sensitization did not regulate the death receptors DR4 and DR5. Moreover, BRD4 inhibition can block TRAIL-induced IKK activation by suppressing the transcriptional activity of NF-κB. These findings indicate that targeting combination therapy with TRAIL and BRD4 inhibitors can be a promising strategy to overcome TRAIL resistance in NSCLC.

Shi L ，Xiong Y ，Hu X ，Wang Z ，Xie C ... -  《International Journal of Medical Sciences》

Phytosphingosine in combination with TRAIL sensitizes cancer cells to TRAIL through synergistic up-regulation of DR4 and DR5.

Choi SY ，Kim MJ ，Chung HY ，Lee SJ ，Jang YJ ... -  《ONCOLOGY REPORTS》

Inhibition of BET bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptotic agents.

Klingbeil O ，Lesche R ，Gelato KA ，Haendler B ，Lejeune P ... -  《Cell Death & Disease》

ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer.

Yang J ，Yang C ，Zhang S ，Mei Z ，Shi M ，Sun S ，Shi L ，Wang Z ，Wang Y ，Li Z ，Xie C ... -  《-》

BET inhibitors combined with chemotherapy synergistically inhibit the growth of NSCLC cells.

Zhou X ，Sun T ，Meng Y ，Luo J ，Chen J ，Xia B ，Zhang Z ，Cheng Z ，Wang X ... -  《-》