GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1

被引：75
作者：
Kumar, Krishan [1 ,3 ]
Raza, Sania S. [1 ]
Knab, Lawrence M. [2 ]
Chow, Christina R. [1 ,4 ]
Kwok, Benjamin [1 ]
Bentrem, David J. [2 ,3 ,4 ]
Popovic, Relja [1 ]
Ebine, Kazumi [1 ,3 ]
Licht, Jonathan D. [1 ,4 ]
Munshi, Hidayatullah G. [1 ,3 ,4 ]
机构：
[1] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA
[2] Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA
[3] Jesse Brown VA Med Ctr, Chicago, IL 60612 USA
[4] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA
来源：
SCIENTIFIC REPORTS | 2015年 / 5卷
关键词：
EPITHELIAL-MESENCHYMAL TRANSITION; DRUG-RESISTANCE; THERAPEUTIC TARGET; PROTEIN; GROWTH; SENSITIVITY; ACTIVATION; APOPTOSIS; HEDGEHOG; PROLIFERATION;
D O I：
10.1038/srep09489
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
JQ1 and I-BET151 are selective inhibitors of BET bromodomain proteins that have efficacy against a number of different cancers. Since the effectiveness of targeted therapies is often limited by development of resistance, we examined whether it was possible for cancer cells to develop resistance to the BET inhibitor JQ1. Here we show that pancreatic cancer cells developing resistance to JQ1 demonstrate cross-resistance to I-BET151 and insensitivity to BRD4 downregulation. The resistant cells maintain expression of c-MYC, increase expression of JQ1-target genes FOSL1 and HMGA2, and demonstrate evidence of epithelial-mesenchymal transition (EMT). However, reverting EMT fails to sensitize the resistant cells to JQ1 treatment. Importantly, the JQ1-resistant cells remain dependent on c-MYC that now becomes co-regulated by high levels of GLI2. Furthermore, downregulating GLI2 re-sensitizes the resistant cells to JQ1. Overall, these results identify a mechanism by which cancer cells develop resistance to BET inhibitors.
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页数：9
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