JQ1 synergizes with the Bcl-2 inhibitor ABT-263 against MYCN-amplified small cell lung cancer
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Huogang Wang1,2,3,*, Bo Hong1,3,*, Xuemin Li1,3, Ke Deng1,2,3, Hong Li1,3, Vivian Wai Yan Lui4 and Wenchu Lin1,3
1High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P.R. China
2University of Science and Technology of China, Hefei 230036, Anhui, P.R. China
3Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, P.R. China
4School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China
Wenchu Lin, email: [email protected]
Keywords: small cell lung cancer, N-Myc, Bcl-2, JQ1, ABT-263
Received: April 05, 2017 Accepted: August 26, 2017 Published: September 21, 2017
Small cell lung cancer (SCLC) is a clinically aggressive cancer with very poor prognosis. Amplification of MYC family genes and overexpression of Bcl-2 protein are common in SCLC, and they are likely therapeutic targets for SCLC. Previous clinical study showed that single agent targeting Bcl-2 with ABT-263 was of 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 MYCN-amplified SCLC cells were highly sensitive to a Bromodomain and Extra-Terminal domain (BET) inhibitor JQ1, which was able to inhibit N-Myc protein expression. The inhibition of N-Myc by JQ1 induced the expression of Bim, and thereby sensitizing MYCN-amplified SCLC cells to ABT-263. The 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 can be employed for MYCN-amplified SCLC with high efficacy.
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