ArticleScientific reports2017
Combined inhibition of MEK and nuclear ERK translocation has synergistic antitumor activity in melanoma cells.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
- Mechanisms that matter: unbiased cellular screening for degraders.npj drug discovery · 2025Review
- Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy.IUBMB life · 2024Review
- Review
- Exploring the In Vitro and In Vivo Therapeutic Potential of BRAF and MEK Inhibitor Combination in NRAS-Mutated Melanoma.Cancers · 2023Article
- Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy.Molecules (Basel, Switzerland) · 2021Review
- Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation.International journal of molecular sciences · 2020Review
- Synergistic inhibition of MEK and reciprocal feedback networks for targeted intervention in malignancy.Cancer biology & medicine · 2019Article
- Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer.International journal of molecular sciences · 2019Review
- Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors.JCI insight · 2018Article
- Combination of EZH2 and MEK inhibitors as an effective therapy for neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.Neuro-oncology advancesArticle
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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