Targeting N-Myc By JQ1 Synergizes With The Bcl-2 Inhibitor ABT-263 Against MYCN-amplified Small Cell Lung Cancer

Small cell lung cancer(SCLC)is a clinically aggressive cancer with very poor prognosis.Overexpression of the anti-apoptotic Bcl-2 protein is common in SCLC,making it a potential therapeutic targets.Previous clinical study showed that single agent targeting Bcl-2 with ABT-263 had limited efficacy in SCLC.In this study,we demonstrated for the first time that co-targeting of N-Myc and Bcl-2 resulted in marked synergistic antitumor effects in MYCN-amplified SCLC.We found that a BET bromodomain inhibitor JQ1 was able to inhibit N-Myc protein expression in MYCN-amplified SCLC.The inhibition of N-Myc by JQ1 induced the expression of Bim,a pro-apoptotic protein in MYCN-amplified SCLC cells.Further,this JQ1-induced Bim up-regulation sensitized MYCN-amplified SCLC cells to ABT-263,and knockdown on Bim by siRNA reduced this JQ1/ABT-263 induced cell death.ABT-263 and JQ1 co-treatment in MYCN-amplified SCLC cells markedly disrupted Bim/Bcl-2 interaction,and prevented Bim’s interaction with Mcl-1.Importantly,this JQ1/ABT-263 co-targeting substantially inhibited the growth of MYCN-amplified SCLC xenografts in vivo.Our study demonstrates a new JQ-1/ABT-263 co-targeting strategy that might be employed for MYCN-amplified SCLC with high efficacy.