The Role of Pigmentation and Oncogenic BRAF in Melanoma
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CitationMitra, Devarati. 2012. The Role of Pigmentation and Oncogenic BRAF in Melanoma. Doctoral dissertation, Harvard University.
AbstractBRAF(V600E), the most commonly mutated oncogene in melanoma, is found in about half of patients. By hyperactivating the MAPK pathway, this mutation promotes cell growth and proliferation. Melanocytic BRAF(V600E) alone, however, is insufficient to cause melanoma and rather promotes the development of benign nevi (moles). The goal of our initial studies was to better understand how genetic and environmental risk factors interact with the BRAF(V600E) oncogene to induce melanoma. The two most prominent risk factors for melanoma development are exposure to ultraviolet (UV) radiation and pale skin pigmentation; particularly in the case of individuals with the “redhead” phenotype, who carry inactivating mutations in the MC1R G-protein coupled receptor. It has commonly been thought that redheads are at highest risk for melanoma development due to poor protection from genotoxic UV radiation from the sun. Using a melanocyte-specific, inducible Braf(V600E) mouse model, we have shown that an inactivating mutation in Mc1r which causes a redhead phenotype in mice, confers a significant UV-independent elevation in melanoma risk, relative to black and albino animals. The mechanism of accelerated UV-independent oncogenesis was found to be dependent on the synthesis of the red/yellow pheomelanin pigment. While these experiments were on-going, a novel small molecule inhibitor of the BRAF(V600E) oncogene, vemurafenib, began showing promising results in clinical trials. The observation that half of patients were experiencing significant tumor regression was unprecedented, but was soon followed by vemurafenib-resistant disease progression. Based on the fact that acquired drug resistance is a major obstacle to good therapeutic outcomes, we began investigating mechanisms of BRAF inhibitor resistance. A panel of BRAF(V600E) human melanoma cell lines that were initially sensitive to PLX4720 (a pre-clinical analog of vemurafenib), were chronically treated with the oncogenic BRAF inhibitor until resistance developed. These paired resistant and sensitive cell lines were characterized in terms of drug sensitivity and activation of cell signaling pathways. Multiple different patterns of drug resistance were found. The diversity of resistance mechanisms in these studies agrees with the diversity which others have found in the literature, suggesting that melanoma cells may be uniquely adaptable to circumventing BRAF(V600E) oncogene addiction.
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