Molecular mechanisms underlying BRAF inhibitors resistance in melanoma

Melanoma represents the most lethal form of skin cancer. About 50% of melanomas are characterized by activating mutations of the BRAF oncogene resulting in the constitutive activation of the MAP kinase (MAPK) signaling cascade. The development of drugs that specifically target mutated BRAF protein (BRAF inhibitors; BRAFi) has dramatically changed the clinical management of melanoma patients carrying these mutations. In fact, BRAFi were proven effective in increasing melanoma patients’ survival, underscoring the key role of MAPK signaling as a driver of these tumors. However, within few months of treatment, BRAF-mutated melanoma patients stop responding to these “targeted therapies” because of acquired resistance mechanisms ensuing in cancer cells. Therefore, the clarification of the molecular mechanisms underlying melanoma resistance to BRAFi is of vital importance for the design of more effective therapeutic strategies aimed to the eradication of these tumors. In this work we show that multiple molecular mechanisms can be responsible for BRAFi resistance in melanoma, including alterations in epigenetic mechanisms (loss of BOP1), and aberrant expression of microRNAs (miRNA-211). We also show that many resistance mechanisms to BRAFi converge on an increase in the levels of Reactive Oxygen Species (ROS) within tumor cells. This can be therapeutically exploited to selectively eradicate BRAFi-resistant cells via a further increase of their ROS levels by a clinically approved Histone Deacetylase inhibitor (Vorinostat). The experimental evidence emerging from the latter study provides the basis for an ongoing clinical trial on melanoma patients carrying activating BRAF mutations.