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PURPOSE To evaluate the effects of BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma. EXPERIMENTAL DESIGN Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10 to 14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF + MEK(More)
Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome(More)
In three years, four drugs have gained regulatory approval for the treatment of metastatic and unresectable melanoma, with at least seven other drugs having recently completed, currently in, or soon to be in phase III clinical testing. This amazing achievement has been made following a remarkable increase of knowledge in molecular biology and immunology(More)
To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context,(More)
While response rates to BRAF inhibitiors (BRAFi) are high, disease progression emerges quickly. One strategy to delay the onset of resistance is to target anti-apoptotic proteins such as BCL-2, known to be associated with a poor prognosis. We analyzed BCL-2 family member expression levels of 34 samples from 17 patients collected before and 10 to 14 days(More)
There have been significant advances with regard to BRAF-targeted therapies against metastatic melanoma. However, the majority of patients receiving BRAF inhibitors (BRAFi) manifest disease progression within a year. We have recently shown that melanoma patients treated with BRAFi exhibit an increase in melanoma-associated antigens and in CD8+(More)
Kaposi sarcoma-associated herpesvirus infection is associated with the development of 3 proliferative diseases: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. These conditions are also intimately associated with human immunodeficiency virus infection, and important synergistic interactions between these 2 viruses have been(More)
Since the initial discovery that a subset of patients with cutaneous melanoma harbor BRAF mutations, substantial research has been focused on determining the pathologic consequences of BRAF mutations, optimizing diagnostic techniques to identify these mutations, and developing therapeutic interventions to inhibit the function of this target in(More)
Melanoma harboring BRAF mutations frequently develop resistance to BRAF inhibitors, limiting the impact of treatment. Here, we establish a mechanism of resistance and subsequently identified a suitable drug combination to overcome the resistance. Single treatment of BRAF mutant melanoma cell lines with vemurafenib or dabrafenib (BRAF inhibitors) alone or in(More)
PURPOSE Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. EXPERIMENTAL DESIGN We conducted a phase II study of nilotinib 400 mg twice a day in(More)