Decitabine limits escape from MEK inhibition in uveal melanoma

Jessica Gonçalves, Michael F. Emmons, Fernanda Faião-Flores, Andrew E. Aplin, J. William Harbour, Jonathan D. Licht, Márcia R. Wink, Keiran S.M. Smalley

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalPigment Cell and Melanoma Research
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

decitabine
Mitogen-Activated Protein Kinase Kinases
Methyltransferases
DNA
Cell Survival
Organoids
Galactosidases
Histone Acetyltransferases
Cells
Chromosome Segregation
Apoptosis Regulatory Proteins
Spindle Apparatus
Drug Delivery Systems
Uveal melanoma
Heterografts
Epigenomics
DNA Damage
Chromosomes

Keywords

  • adaptation
  • DNMT
  • epigenetics
  • MEK
  • uveal

ASJC Scopus subject areas

  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Dermatology

Cite this

Gonçalves, J., Emmons, M. F., Faião-Flores, F., Aplin, A. E., Harbour, J. W., Licht, J. D., ... Smalley, K. S. M. (Accepted/In press). Decitabine limits escape from MEK inhibition in uveal melanoma. Pigment Cell and Melanoma Research. https://doi.org/10.1111/pcmr.12849

Decitabine limits escape from MEK inhibition in uveal melanoma. / Gonçalves, Jessica; Emmons, Michael F.; Faião-Flores, Fernanda; Aplin, Andrew E.; Harbour, J. William; Licht, Jonathan D.; Wink, Márcia R.; Smalley, Keiran S.M.

In: Pigment Cell and Melanoma Research, 01.01.2019.

Research output: Contribution to journalArticle

Gonçalves, J, Emmons, MF, Faião-Flores, F, Aplin, AE, Harbour, JW, Licht, JD, Wink, MR & Smalley, KSM 2019, 'Decitabine limits escape from MEK inhibition in uveal melanoma', Pigment Cell and Melanoma Research. https://doi.org/10.1111/pcmr.12849
Gonçalves, Jessica ; Emmons, Michael F. ; Faião-Flores, Fernanda ; Aplin, Andrew E. ; Harbour, J. William ; Licht, Jonathan D. ; Wink, Márcia R. ; Smalley, Keiran S.M. / Decitabine limits escape from MEK inhibition in uveal melanoma. In: Pigment Cell and Melanoma Research. 2019.
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