Combined inhibition of MEK and nuclear ERK translocation has synergistic antitumor activity in melanoma cells

Rand Arafeh, Karen Flores, Alona Keren-Paz, Galia Maik-Rachline, Naomi Gutkind, Steven Rosenberg, Rony Seger, Yardena Samuels

Research output: Contribution to journalArticle

Abstract

Genetic alterations in BRAF, NRAS and NF1 that activate the ERK cascade, account for over 80% of metastatic melanomas. However, ERK cascade inhibitors have been proven beneficial almost exclusively for BRAF mutant melanomas. One of the hallmarks of the ERK cascade is the nuclear translocation of ERK1/2, which is important mainly for the induction of proliferation. This translocation can be inhibited by the NTS-derived peptide (EPE) that blocks the ERK1/2-importin7 interaction, inhibits the nuclear translocation of ERK1/2, and arrests active ERK1/2 in the cytoplasm. In this study, we found that the EPE peptide significantly reduced the viability of not only BRAF, but also several NRAS and NF1 mutant melanomas. Importantly, combination of the EPE peptide and trametinib showed synergy in reducing the viability of some NRAS mutant melanomas, an effect driven by the partial preservation of negative feedback loops. The same combination significantly reduced the viability of other melanoma cells, including those resistant to mono-treatment with EPE peptide and ERK cascade inhibitors. Our study indicates that targeting the nuclear translocation of ERK1/2, in combination with MEK inhibitors can be used for the treatment of different mutant melanomas.

Original languageEnglish (US)
Article number16345
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

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Mitogen-Activated Protein Kinase Kinases
Melanoma
Peptides
Cytoplasm

ASJC Scopus subject areas

  • General

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Arafeh, R., Flores, K., Keren-Paz, A., Maik-Rachline, G., Gutkind, N., Rosenberg, S., ... Samuels, Y. (2017). Combined inhibition of MEK and nuclear ERK translocation has synergistic antitumor activity in melanoma cells. Scientific Reports, 7(1), [16345]. https://doi.org/10.1038/s41598-017-16558-0

Combined inhibition of MEK and nuclear ERK translocation has synergistic antitumor activity in melanoma cells. / Arafeh, Rand; Flores, Karen; Keren-Paz, Alona; Maik-Rachline, Galia; Gutkind, Naomi; Rosenberg, Steven; Seger, Rony; Samuels, Yardena.

In: Scientific Reports, Vol. 7, No. 1, 16345, 01.12.2017.

Research output: Contribution to journalArticle

Arafeh, R, Flores, K, Keren-Paz, A, Maik-Rachline, G, Gutkind, N, Rosenberg, S, Seger, R & Samuels, Y 2017, 'Combined inhibition of MEK and nuclear ERK translocation has synergistic antitumor activity in melanoma cells', Scientific Reports, vol. 7, no. 1, 16345. https://doi.org/10.1038/s41598-017-16558-0
Arafeh, Rand ; Flores, Karen ; Keren-Paz, Alona ; Maik-Rachline, Galia ; Gutkind, Naomi ; Rosenberg, Steven ; Seger, Rony ; Samuels, Yardena. / Combined inhibition of MEK and nuclear ERK translocation has synergistic antitumor activity in melanoma cells. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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