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Sci Rep. 2015 Mar 25;5:9489. doi: 10.1038/srep09489.

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

Author information

1
1] Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Ave, Chicago, IL 60611 [2] Jesse Brown VA Medical Center, 820 S. Damen Ave, Chicago, IL 60612.
2
Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Ave, Chicago, IL 60611.
3
Department of Surgery, Feinberg School of Medicine, Northwestern University, 676 N. St. Clair St, Chicago, IL 60611.
4
1] Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Ave, Chicago, IL 60611 [2] The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 303 E. Superior Ave, Chicago, IL 60611.
5
1] Department of Surgery, Feinberg School of Medicine, Northwestern University, 676 N. St. Clair St, Chicago, IL 60611 [2] Jesse Brown VA Medical Center, 820 S. Damen Ave, Chicago, IL 60612 [3] The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 303 E. Superior Ave, Chicago, IL 60611.
6
1] Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Ave, Chicago, IL 60611 [2] Jesse Brown VA Medical Center, 820 S. Damen Ave, Chicago, IL 60612 [3] The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 303 E. Superior Ave, Chicago, IL 60611.

Abstract

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.

PMID:
25807524
PMCID:
PMC4452877
DOI:
10.1038/srep09489
[Indexed for MEDLINE]
Free PMC Article

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