@article{de87690a73c244b98217700923019f67,
title = "Decitabine limits escape from MEK inhibition in uveal melanoma",
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.",
keywords = "DNMT, MEK, adaptation, epigenetics, uveal",
author = "Jessica Gon{\c c}alves and Emmons, {Michael F.} and Fernanda Fai{\~a}o-Flores and Aplin, {Andrew E.} and Harbour, {J. William} and Licht, {Jonathan D.} and Wink, {M{\'a}rcia R.} and Smalley, {Keiran S.M.}",
note = "Funding Information: This work is supported by the Bankhead-Coley Program of the State of Florida 7BC05 (to KSMS, JWH and JDL). It has been also supported in part by the Flow Cytometry Core Facility, the Analytic Microscopy Core Facility, the Proteomics and Metabolomics Core Facility, the Molecular Genomics Core and the Tissue Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292). This work has also been supported in part by Bolsista da Capes PDSE - Edital no 19/2016 Processo no 88881.131638/2016-01. Uveal melanoma studies in the Aplin laboratory are funded by a Melanoma Research Alliance team science award and Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., Trustee. Funding Information: This work is supported by the Bankhead‐Coley Program of the State of Florida 7BC05 (to KSMS, JWH and JDL). It has been also supported in part by the Flow Cytometry Core Facility, the Analytic Microscopy Core Facility, the Proteomics and Metabolomics Core Facility, the Molecular Genomics Core and the Tissue Core Facility at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30‐CA076292). This work has also been supported in part by Bolsista da Capes PDSE ‐ Edital no 19/2016 Processo no 88881.131638/2016‐01. Uveal melanoma studies in the Aplin laboratory are funded by a Melanoma Research Alliance team science award and Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., Trustee. Publisher Copyright: {\textcopyright} 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd",
year = "2020",
month = may,
day = "1",
doi = "10.1111/pcmr.12849",
language = "English (US)",
volume = "33",
pages = "507--514",
journal = "Pigment Cell and Melanoma Research",
issn = "1755-1471",
publisher = "Wiley-Blackwell",
number = "3",
}