Alterations of mitochondrial morphology and dynamics in cancer: understanding of tumor biology and prospecting new therapeutic targets

Abstract

Melanoma is a tumor originated in melanocytes predisposed to the accumulation of DNA damage, resulting in genetic mutations that favor its malignancy, such as the stimulation of blood vessel growth, immune response evasion, tumor invasion and metastasis. Although potentially curable sometimes, malignant melanoma is an aggressive type of cancer, with a high mortality resistance development rate to therapy. The most prevalent oncogenic mutations are already known in human melanoma, among them in B-Raf, N-Ras and c-Kit. The mutated oncoprotein BRAF (V600E) is the most prevalent genetic alteration in this type of cancer (> 50%) and results in the constant activation of BRAF conferring proliferative advantages to the melanoma cells. Among the recent therapeutic advances for the treatment of melanoma is the targeted therapy and BRAF inhibitors were developed, including the well-known drug vemurafenib. Significant tumor regression associated to improved survival rates of patients affected by melanomas with BRAF mutation in response to vemurafenib treatment, clearly demonstrates the essential role of the activation of this oncogene in the maintenance of melanoma. However, most patients treated with vemurafenib have recurrence of drug-resistant lethal melanoma. Thus, the understanding of resistance mechanisms as well as to develop tools to prevent or reverse it is of pivotal importance. Thus, in this project we will evaluate the susceptibility of BRAF and NRAS mutated human melanomas to vemurafenib, and comparatively study the alterations in mitochondrial morphology and dynamics induced by the inhibition of BRAF, in order to bring advances in the tumor biology knowledge of these types of cancer. Also, we will prospect new therapeutic targets and possible combined therapies to increase the success of the target therapy in susceptible cells and overcome the resistance of non-responsive melanoma cells to vemurafenib. (AU)