Melanoma is the most lethal form of skin cancer. Therapeutic alternatives to metastatic melanoma are very limited. Activation of RAS pathway appears to be the central motor driving melanoma development and maintenance, where BRAFV600E and NRASQ61L are found in ~ 50% and 20% of human melanomas, respectively. Although, these mutually exclusive mutations affect the same pathway emerging preclinical and clinical evidence suggests that NRASQ61L mutant melanomas have patterns of signal transduction and biological behavior that is distinct from BRAFV600E mutant melanomas. These patterns include a differential response to metabolic stress. We believe that successful exploitation of mutations in melanoma will be dependent on understanding not only mutations and their frequency but their genetic and biochemical/metabolic context as well. The overall objective of the present project is to find novel therapeutic alternatives to treat NRASQ61L and/or BRAFV600E mutant melanoma tumours by targeting specific metabolic enzymes, such as Aldehyde Deshydrogenases, with potential synthetic lethality.
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