Mitogen-activated protein kinase (MEK) inhibitors to treat melanoma alone or in combination with other kinase inhibitors

ABSTRACT

Introduction: Malignant melanoma (MM) is an aggressive disease with a rapidly rising incidence due to neoplasm of melanocytes. Molecular targeted therapies have demonstrated lower toxicity and improved overall survival versus conventional therapies of MM. The revealing of mutations in the BRAF/MEK/ERK pathway has led to the development of BRAF inhibitors such as vemurafenib and dabrafenib for the treatment of cutaneous MM. Though, progression of resistance to these agents has prompted attempts to target downstream proteins in this pathway. Trametinib, a MEK1/2 inhibitor, was approved in 2013 for the treatment of BRAF V600E/K mutation-positive unresectable or metastatic cutaneous melanoma patients.

Areas covered: The aim of the current review is to present an update on the role of MEK in progressive melanomas and summarize latest results of clinical studies with innovative MEK inhibitors and/or combined approaches with other kinase inhibitors such as BRAF inhibitors in the treatment of MM.

Expert opinion: Two combined treatments (i.e. trametinib plus dabrafenib and vemurafenib plus cobimetinib) target two different kinases in the BRAF/MEK/ERK pathway. The simultaneous prohibition of both MEK and BRAF is associated with more durable response rate than BRAF monotherapy and can overcome acquired resistance.

KEYWORDS:

• Binimetinib
• Cobimetinib
• Melanoma
• MAPK pathway
• MEK
• Pimasertib
• Selumetinib
• systematic review
• Trametinib

Article highlights

• MEK-1/-2 are key kinases in the MAPK signaling pathway, which is involved in a variety of cellular processes, such as cell division and cell death.

• Trametinib was the first MEKi both as a single agent (approved in 2013) and in combination with dabrafenib (approved in 2014) for the treatment of previously untreated metastatic BRAF-mutated melanoma.

• Clinical studies using MEKi as monotherapy has been unsatisfactory in patients previously treated with a BRAFi. So this therapy should be set for previously untreated patients.

• Combined BRAFi and MEKi therapy shows better clinical efficacy and fewer BRAF inhibition-related side effects than BRAFi monotherapy, and may have a role in patients with disease progression on prior BRAFi treatment.

• Based on preliminary data, binimetinib has demonstrated hopeful clinical activity in melanoma patients with NRAS-mutant tumors.

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Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded