JQ1 synergizes with the Bcl-2 inhibitor ABT-263 against MYCN-amplified small cell lung cancer

Huogang Wang, Bo Hong, Xuemin Li, Ke Deng, Hong Li, Vivian Wai Yan Lui, Wenchu Lin

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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 cotreatment 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.

Original languageEnglish (US)
Pages (from-to)86312-86324
Number of pages13
JournalOncotarget
Volume8
Issue number49
DOIs
StatePublished - Oct 17 2017
Externally publishedYes

Keywords

  • ABT-263
  • Bcl-2
  • JQ1
  • N-Myc
  • Small cell lung cancer

ASJC Scopus subject areas

  • Oncology

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