Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma, and lacks effective treatments.,Here we genomically profile metastatic tumors and infiltrating lymphocytes.,BAP1 alterations are overrepresented and found in 29/32 of cases.,Reintroducing a functional BAP1 allele into a deficient patient-derived cell line, reveals a broad shift towards a transcriptomic subtype previously associated with better prognosis of the primary disease.,One outlier tumor has a high mutational burden associated with UV-damage.,CDKN2A deletions also occur, which are rarely present in primaries.,A focused knockdown screen is used to investigate overexpressed genes associated withcopy number gains.,Tumor-infiltrating lymphocytes are in several cases found tumor-reactive, but expression of the immune checkpoint receptors TIM-3, TIGIT and LAG3 is also abundant.,This study represents the largest whole-genome analysis of uveal melanoma to date, and presents an updated view of the metastatic disease.,The genetics of uveal melanoma has mainly been studied in primary tumours.,In this study, the authors perform whole genome sequencing as well as immune cell profiling of biopsy samples obtained from metastatic uveal melanoma patients, providing an updated genomic landscape of these advanced lesions.
Vemurafenib/PLX4032, a selective inhibitor of mutant BRAFV600E, constitutes a paradigm shift in melanoma therapy.,Unfortunately, acquired resistance, which unavoidably occurs, represents one major limitation to clinical responses.,Recent studies have highlighted that vemurafenib activated oxidative metabolism in BRAFV600E melanomas expressing PGC1α.,However, the oxidative state of melanoma resistant to BRAF inhibitors is unknown.,We established representative in vitro and in vivo models of human melanoma resistant to vemurafenib including primary specimens derived from melanoma patients.,Firstly, our study reveals that vemurafenib increased mitochondrial respiration and ROS production in BRAFV600E melanoma cell lines regardless the expression of PGC1α.,Secondly, melanoma cells that have acquired resistance to vemurafenib displayed intrinsically high rates of mitochondrial respiration associated with elevated mitochondrial oxidative stress irrespective of the presence of vemurafenib.,Thirdly, the elevated ROS level rendered vemurafenib-resistant melanoma cells prone to cell death induced by pro-oxidants including the clinical trial drug, elesclomol.,Based on these observations, we propose that the mitochondrial oxidative signature of resistant melanoma constitutes a novel opportunity to overcome resistance to BRAF inhibition.