For the first time new treatments in melanoma have produced significant responses in advanced diseases, but 30-90% of melanoma patients do not respond or eventually relapse after the initial response to the current treatments.,The resistance of these melanomas is likely due to tumor heterogeneity, which may be explained by models such as the stochastic, hierarchical, and phenotype-switching models.,This review will discuss the recent advancements in targeting BCL-2 family members for cancer treatments, and how this approach can be applied as an alternative option to combat melanoma, and overcome melanoma relapse or resistance in current treatment regimens.
Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas.,In this study, we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS.,Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects.,We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling.,Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164).,We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C.,Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C.,Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma.,DOI:http://dx.doi.org/10.7554/eLife.01460.001,Cancer is a leading cause of death worldwide, and although cancer can have many causes, mutations to a small number of genes are often responsible for a large number of cancer cases.,For example, about 70% of cases of the deadliest form of skin cancer have mutations in two specific genes.,Many cancer-causing genes are regulated by small RNA molecules that impede the function of other genes by blocking the machinery that turns a gene into a functional protein.,However, until recently there was a limited understanding of the role of these microRNAs in the skin cancers caused by the most common mutations.,Now, Forloni et al. have looked at all the microRNAs present in cells carrying a mutated form of the one of these genes, and compared these with the microRNAs found in healthy cells.,A microRNA, called miR-146a, was discovered to be much more common in the cancer cells.,Moreover, production of this microRNA was increased by the two cancer-causing mutations.,Forloni et al. found that increasing production of this microRNA caused human skin cancer cells to grow faster, and also caused tumors to develop in mice.,Reducing the level of miR-146a had the opposite effect.,Forloni et al. also looked at cancer cells taken from individuals at different stages of skin cancer and found that, as the disease progresses, an unprocessed form of miR-146a tends to acquire a mutation, which leads to much higher levels of the active, processed form of miR-146a in the cancer cells.,High levels of miR-146a also switched off a gene that encodes for a protein that, in turn, switches off a protein called NOTCH that is linked to skin cancer.,As such, excess miR-146a actually increases the activation of the NOTCH protein.,These results led Forloni et al. to test if delivering drugs that block the production of miR-146a by inhibiting skin cancer-causing genes, along with other drugs that inhibit the Notch signaling pathway, could be more effective than treatment with either drug on its own.,The combined treatment was very effective against human skin cancer cells and could represent a promising development in the treatment of this disease.,DOI:http://dx.doi.org/10.7554/eLife.01460.002