Signaling pathways in melanoma biology and new targeted therapeutic approaches

Abstract

Despite the broad prevention programs and early detection and therapy progress, melanoma of skin is still responsible for 0.6% of deaths caused by tumour disease. Every year 300,000 patients are diagnosed and 60,000 die from the most malignant of skin cancer. Generally, melanoma is formed as a result of mutation of growth pathways responsible for proliferation and apoptosis. One of the most investigated pathway, mutated in 90% of melanomas, is RAS > RAF > MEK > ERK also known as mitogen-activated protein kinase (MAPK) pathway. The second one is phosphoinositide-3-OH kinase (PI3K) pathway. The better understanding of melanoma biology resulted in research of inhibitors, which can affect presented pathways and prevent uncontrolled proliferation of melanoma. The BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitor trametinib seem to be the most successful ones. Recent advances in biology of melanoma provided new interesting therapeutic targets. One of the most inquiring is microphthalmia associated transcription factor (MITF), the principal regulator of melanocyte lineage. MITF perform the role of so-called ‘survival’ or ‘addiction’ oncogene. Moreover, the interleukin-1 receptor-associated kinases (IRAKs) might clarify the connection between the inflammatory environment and melanoma carcinogenesis. IRAKs play a key role as mediators of toll-like receptor (TLR) and interleukin-1 receptor (IL1R) in inflammation signalling processes. Moreover, it was observed that metformin cause cell cycle arrest in melanoma cells, secondly leading to activation of autophagy and apoptosis. Although due to targeted and immunotherapy the prognosis of patients with metastatic melanoma is incomparably better, melanoma in its advanced stadium is still predominantly lethal. Therefore, the most present research concentrates on acquired resistance against targeted therapy.