Decitabine limits escape from MEK inhibition in uveal melanoma

Pigment Cell Melanoma Res. 2020 May;33(3):507-514. doi: 10.1111/pcmr.12849. Epub 2019 Dec 6.


MEK inhibitors (MEKi) demonstrate anti-proliferative activity in patients with metastatic uveal melanoma, but responses are short-lived. In the present study, we evaluated the MEKi trametinib alone and in combination with drugs targeting epigenetic regulators, including DOT1L, EZH2, LSD1, DNA methyltransferases, and histone acetyltransferases. The DNA methyltransferase inhibitor (DNMTi) decitabine effectively enhanced the anti-proliferative activity of trametinib in cell viability, colony formation, and 3D organoid assays. RNA-Seq analysis showed the MEKi-DNMTi combination primarily affected the expression of genes involved in G1 and G2/2M checkpoints, cell survival, chromosome segregation and mitotic spindle. The DNMTi-MEKi combination did not appear to induce a DNA damage response (as measured by γH2AX foci) or senescence (as measured by β-galactosidase staining) compared to either MEKi or DNMTi alone. Instead, the combination increased expression of the CDK inhibitor p21 and the pro-apoptotic protein BIM. In vivo, the DNMTi-MEKi combination was more effective at suppressing growth of MP41 uveal melanoma xenografts than either drug alone. Our studies indicate that DNMTi may enhance the activity of MEKi in uveal melanoma.

Keywords: DNMT; MEK; adaptation; epigenetics; uveal.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Line, Tumor
  • Decitabine / pharmacology
  • Decitabine / therapeutic use*
  • Female
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / enzymology*
  • Melanoma / pathology
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridones / pharmacology
  • Pyridones / therapeutic use
  • Pyrimidinones / pharmacology
  • Pyrimidinones / therapeutic use
  • Uveal Neoplasms / drug therapy*
  • Uveal Neoplasms / enzymology*
  • Uveal Neoplasms / pathology
  • Xenograft Model Antitumor Assays


  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • trametinib
  • Decitabine
  • Mitogen-Activated Protein Kinase Kinases

Supplementary concepts

  • Uveal melanoma