BRAF is the most commonly mutated oncogene in melanoma, with the BRAFV600 mutation occurring in approximately 50% of melanoma patients. The development of therapies, such as Vemurafenib, targeting the BRAFV600 mutation represents a clear example of successful targeting of an oncogene for the treatment of cancer. However, despite initial profound responses, acquisition of resistance to BRAF inhibitors invariably occurs and represents a major challenge in the clinical management of BRAFV600 melanoma. Work from our laboratory and others have shown that BRAFV600 regulates aerobic glycolysis in melanoma, and that treatment with Vemurafenib can suppress this glycolytic response. Importantly, adaptive metabolic reprogramming has also been associated with development of BRAF inhibitor resistance, highlighting the need for further investigation of metabolism as a potential therapeutic target in the treatment of BRAFV600 melanoma patients.
In order to further explore BRAF-driven glycolysis we have performed a genome-wide siRNA screen in BRAFV600 melanoma cells treated with DMSO or Vemurafenib in parallel for 48hrs. Both cell viability and glycolytic responses (as assessed by lactate production per cell) were measured using a multi-parameter imaging and colorimetric screening approach. By mapping this phenotypic dataset to protein interaction networks we have generated a systems-level view of pathways and protein complexes that regulate BRAF-driven glycolysis in BRAF mutant melanoma. This approach uncovered a novel role for YB-1, a major node in the RNA metabolism pathway, in metabolic reprogramming in BRAF mutant melanoma, and significantly, depletion of YB-1 specifically synergises with Vemurafenib to potently suppress glycolysis. We propose that inactivation of the YB-1 pathway represents an attractive therapeutic target to make BRAF inhibitors more effective in the context of BRAFV600 mutant melanoma.