RAS/RAF/MEK/ERK and PI3K/PTEN/AKT Signaling in Malignant Melanoma Progression and Therapy

Abstract

Cutaneous malignant melanoma is one of the most serious skin cancers and is highly invasive and markedly resistant to conventional therapy. Melanomagenesis is initially triggered by environmental agents including ultraviolet (UV), which induces genetic/epigenetic alterations in the chromosomes of melanocytes. In human melanomas, the RAS/RAF/MEK/ERK (MAPK) and the PI3K/PTEN/AKT (AKT) signaling pathways are two major signaling pathways and are constitutively activated through genetic alterations. Mutations of RAF, RAS, and PTEN contribute to antiapoptosis, abnormal proliferation, angiogenesis, and invasion for melanoma development and progression. To find better approaches to therapies for patients, understanding these MAPK and AKT signaling mechanisms of melanoma development and progression is important. Here, we review MAPK and AKT signaling networks associated with melanoma development and progression.

Subcutaneous Adipocytes Promote Melanoma Cell Growth by Activating the Akt Signaling Pathway

“…Increased activation of the PI3K/Akt pathway is found in up to 70% of melanomas (29,49). Akt signaling has been reported to regulate melanoma cell survival, migration, and metastasis and contribute to melanoma chemoresistance to therapy (29,49).…”

“…Akt signaling has been reported to regulate melanoma cell survival, migration, and metastasis and contribute to melanoma chemoresistance to therapy (29,49). Recently, it is reported that Akt in human cancer induced the glycolytic phenotype in cancer cells by phosphorylating hexokinase II to increase its association with voltage-dependent anion channel on the mitochondrial outer membrane (50).…”

Treatment of advanced melanoma - A changing landscape

“…6 In the past decades, however, progress has been made in the understanding of both melanoma pathogenesis and the interaction between cancer and immune cells. The demonstration of aberrant activation of the mitogenactivated protein kinase pathway (MAPK) paved the way for the development of so-called targeted therapies, 7 including the currently available V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) and mitogen-activated protein kinases enzyme (MEK) inhibitors ( Figure 1). 8,9 In parallel, the manipulation of the immune system by blocking ligands and receptors that act as regulators of the T cell activation, the so-called immune checkpoints, exemplified by the cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD1) and its ligand (PD-L1) have become important strategies to control advanced tumors ( Figure 2).…”

“…7,9 In about 75 to 80% of the cases, the mutation occurs in the region that encodes the kinase domain and consists of the substitution of glutamic acid for valine at amino acid 600 (the V600E muta- . 11 In another 20% of the tumors harboring a BRAF mutation, an alternate substitution of lysine for valine occurs (the V600K mutation).…”

“…9,24 Other less common mutations occur in NF1 and c-KIT. 7,9 Initial results of a phase 3 trial comparing binimetinib, a MEKi, to dacarbazine in patients with advanced NRAS mutation tumors, showed an increase in PFS (median PFS 2.8 vs. 1.5 months; HR 0.62; 95CI 0.47-0.80; p<0.001). In this trial, there was no significant difference in overall survival (11 vs. 10 months), although survival data were still immature.…”