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

Abstract

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.

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

“…Consistent with our study, a number of studies demonstrated that combination therapy would be more efficient to inhibit acquired resistance in the process of development and showed better survival benefit . Studies of recent development and obstacles of melanoma with BRAF and MEK inhibition as MAPK pathway inhibitor significantly overcame acquired resistance and had a higher survival rate and a more durable response rate . It had been reported that combination of MEK and BRAF inhibition had improved the quality of life of patient with metastatic melanoma …”

“…21 as MAPK pathway inhibitor significantly overcame acquired resistance and had a higher survival rate and a more durable response rate. 32,33 It had been reported that combination of MEK and BRAF inhibition had improved the quality of life of patient with metastatic melanoma. 34 In our meta-analysis, the occurrence of skin events was significantly reduced in the BRAF and MEK group.…”

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

“…This work also predicted that breaking the negative feedback loop by inhibiting its target RAF will allow MEK inhibitors to work. Indeed, the combination of RAF and MEK inhibitors is now standard in the therapy of metastatic malignant melanoma and other cancer types [5][6][7][8][9][10]. The formula relating input (u) to output (y) shows that the NFA output is dominated by the strength of feedback (F) rather than the amplification (A).…”

“…Prolific work has been done on drugs targeting this pathway and elucidating mechanisms of sensitivity and resistance. As the results have been extensively reviewed [4][5][6][7][8][9][10][11][12][13], we only briefly summarize the salient findings here. Instead, we focus on discussing less well reviewed areas of MAPK signaling and their relevance to drug resistance, i.e., the JNK and p38 MAPK pathways, as well as epigenetic and metabolic changes linked to MAPK signaling.…”

Caspase‑dependent apoptotic death by gadolinium chloride (GdCl3) via reactive oxygen species production and MAPK signaling in rat C6 glioma cells

“…MAPKs are divided into three main subfamilies: ERK, JNK, and p38 MAPKs. Increasing evidence has shown that MAPKs play crucial roles and exhibit cell functions in cell survival, cell proliferation, cell cycle regulation, and apoptotic death (46,47). ERK is involved in cell survival, and JNK and p38 MAPK are thought to mainly promote cell apoptosis (48,49).…”