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.

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