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

Krishan Kumar; Sania S Raza; Lawrence M Knab; Christina R Chow; Benjamin Kwok; David J Bentrem; Relja Popovic; Kazumi Ebine; Jonathan D Licht; Hidayatullah G Munshi

doi:10.1038/srep09489

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

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Apoptosis / drug effects
Azepines / administration & dosage
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / genetics*
Epithelial-Mesenchymal Transition / drug effects*
Gene Expression Regulation, Neoplastic / drug effects
Heterocyclic Compounds, 4 or More Rings / administration & dosage
Humans
Kruppel-Like Transcription Factors / biosynthesis
Kruppel-Like Transcription Factors / genetics*
Nuclear Proteins / biosynthesis
Nuclear Proteins / genetics*
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / pathology
Proto-Oncogene Proteins c-myc / biosynthesis*
Proto-Oncogene Proteins c-myc / genetics
Signal Transduction / drug effects
Transcriptional Activation / drug effects
Triazoles / administration & dosage
Xenograft Model Antitumor Assays
Zinc Finger Protein Gli2

Substances

(+)-JQ1 compound
Azepines
GLI2 protein, human
GSK1210151A
Heterocyclic Compounds, 4 or More Rings
Kruppel-Like Transcription Factors
MYC protein, human
Nuclear Proteins
Proto-Oncogene Proteins c-myc
Triazoles
Zinc Finger Protein Gli2

Abstract

Publication types

MeSH terms

Substances

Grants and funding