MAP kinase signaling and inhibition in melanoma

Abstract

The mitogen-activated protein kinase (MAPK) pathway is critical to oncogenic signaling in the majority of patients with malignant melanoma. Driver mutations in both NRAS and BRAF have important implications for prognosis and treatment. The development of inhibitors to mediators of the MAPK pathway, including those to CRAF, BRAF, and MEK, has led to major advances in the treatment of patients with melanoma. In particular, the selective BRAF inhibitor vemurafenib has been shown to improve overall survival in patients with tumors harboring BRAF mutations. However, the duration of benefit is limited in many patients and highlights the need for understanding the limitations of therapy in order to devise more effective strategies. MEK inhibitors have proven to particularly active in BRAF mutant melanomas also. Emerging knowledge about mechanisms of resistance as well as a more complete understanding of the biology of MAPK pathway signaling provides insight into rational combination regimens and sequences of molecularly targeted therapies.

Activities of multiple cancer-related pathways are associated withBRAFmutation and predict the resistance to BRAF/MEK inhibitors in melanoma cells

“…As an example, about 20 to 40% of patients with BRAF-mutated melanoma do not respond to the BRAFV600E inhibitor PLX4032. [2][3][4][5] Thus, novel treatment strategies and biomarkers for prediction of such drug resistance are urgently needed to improve the response rates and the duration of clinical benefit. In this context, it is interesting that several molecular abnormalities, such as the activation of hepatocyte growth factor (HGF)/MET signaling, amplification of cyclin D1 (CCND1), CDK4-activating mutations, and loss of phosphatase and tensin homolog (PTEN) or retinoblastoma protein (RB1), have been recently found to be associated with the innate resistance to BRAF/MEK signaling inhibitors in a small range of BRAF-mutated cancer cells (reviewed in refs.…”

“…This is the most common mutation in melanoma, occurring in about 50% of cases. 2,3 Several BRAF/MEK signaling pathway inhibitors, including inhibitors selectively against BRAFV600E or its downstream molecular MEK, have shown prominent effects in melanoma patients in recent clinical trials. 2,4 One of the major clinical obstacles in this molecular-targeted therapy is, however, the commonly seen innate drug resistance.…”

“…1 A prominent molecular pathological characteristic of melanoma is that gene mutations in the BRAF/MEK pathway are highly prevalent. 2,3 Among them is the BRAF T1799A, which results in BRAFV600E that possesses constitutively activated BRAF kinase activities. This is the most common mutation in melanoma, occurring in about 50% of cases.…”

Primary sinonasal mucosal melanoma – Case report and literature review

“…Both mutations take part in the mitogen-activated proteinkinase (MAPK) pathway, which is involved in melanoma development 33 . Although both mutations occur in a high percentage in cutaneous melanoma, mucosal melanomas have very low frequencies in BRAF mutation (4%) and higher in NRAS mutation (11%) 15 .…”

Melanoma genotypes and phenotypes get personal

“…35 As BRAF belongs to the MAPK pathway, its increased activation ultimately stimulates MM cellular proliferation. [36][37][38] BRAF mutations have been associated with activation of AKT or loss of PTEN. [39][40][41] Furthermore, aberrations in the G proteins, GNAQ and GNA11, stimulate BRAF and its downstream effector, MEK.…”