Transcriptional targeting of oncogene addiction in medullary thyroid cancer

JCI Insight. 2018 Aug 23;3(16):e122225. doi: 10.1172/jci.insight.122225.

Abstract

Metastatic medullary thyroid cancer (MTC) is incurable and FDA-approved kinase inhibitors that include oncogenic RET as a target do not result in complete responses. Association studies of human MTCs and murine models suggest that the CDK/RB pathway may be an alternative target. The objective of this study was to determine if CDKs represent therapeutic targets for MTC and to define mechanisms of activity. Using human MTC cells that are either sensitive or resistant to vandetanib, we demonstrate that palbociclib (CDK4/6 inhibitor) is not cytotoxic to MTC cells but that they are highly sensitive to dinaciclib (CDK1/2/5/9 inhibitor) accompanied by reduced CDK9 and RET protein and mRNA levels. CDK9 protein was highly expressed in 83 of 83 human MTCs and array-comparative genomic hybridization had copy number gain in 11 of 30 tumors. RNA sequencing demonstrated that RNA polymerase II-dependent transcription was markedly reduced by dinaciclib. The CDK7 inhibitor THZ1 also demonstrated high potency and reduced RET and CDK9 levels. ChIP-sequencing using H3K27Ac antibody identified a superenhancer in intron 1 of RET. Finally, combined inhibition of dinaciclib with a RET kinase inhibitor was synergistic. In summary, we have identified what we believe is a novel mechanism of RET transcription regulation that potentially can be exploited to improve RET therapeutic targeting.

Keywords: Cancer; Endocrinology; Oncology; Thyroid disease; Transcription.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
  • Carcinoma, Neuroendocrine / drug therapy*
  • Carcinoma, Neuroendocrine / genetics
  • Carcinoma, Neuroendocrine / pathology
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Drug Synergism
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Introns / genetics
  • Molecular Targeted Therapy / methods
  • Oncogene Addiction
  • Piperazines / pharmacology
  • Piperazines / therapeutic use
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-ret / antagonists & inhibitors
  • Proto-Oncogene Proteins c-ret / genetics*
  • Proto-Oncogene Proteins c-ret / metabolism
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Pyridinium Compounds / pharmacology
  • Pyridinium Compounds / therapeutic use
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use
  • Thyroid Gland / pathology
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / pathology
  • Tissue Array Analysis
  • Transcription, Genetic / drug effects*

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Piperazines
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyridinium Compounds
  • Quinazolines
  • dinaciclib
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Cyclin-Dependent Kinases
  • palbociclib
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine

Supplementary concepts

  • Thyroid cancer, medullary