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1.
Clin Cancer Res ; 19(5): 1225-31, 2013 Mar 01.
Article in English | MEDLINE | ID: mdl-23307859

ABSTRACT

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 inhibition (dabrafenib + trametinib) and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T-cell markers, and immunomodulatory cytokines. RESULTS: Treatment with either BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8+ T-cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines [interleukin (IL)-6 and IL-8] and an increase in markers of T-cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 was increased on treatment. A decrease in melanoma antigen expression and CD8 T-cell infiltrate was noted at time of progression on BRAF inhibitor alone and was reversed with combined BRAF and MEK inhibition. CONCLUSIONS: Together, these data suggest that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T-cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma.


Subject(s)
Biomarkers, Tumor/genetics , Imidazoles/pharmacology , Indoles/pharmacology , Melanoma-Specific Antigens/metabolism , Melanoma/metabolism , Oximes/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Sulfonamides/pharmacology , Tumor Microenvironment , Apoptosis , Blotting, Western , Cell Line, Tumor , Cell Proliferation , Fluorescent Antibody Technique , Humans , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 1/metabolism , Melanoma/immunology , Melanoma/secondary , Neoplasm Staging , Prognosis , Proto-Oncogene Proteins B-raf/metabolism , Pyridones/pharmacology , Pyrimidinones/pharmacology , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Vemurafenib
2.
Plant Mol Biol ; 61(1-2): 241-53, 2006 May.
Article in English | MEDLINE | ID: mdl-16786304

ABSTRACT

Ubiquitylation is an important biochemical reaction found in all eukaryotic organisms and is involved in a wide range of cellular processes. Conventional ubiquitylation requires the formation of polyubiquitin chains linked through Lys48 of the ubiquitin, which targets specific proteins for degradation. Recently polyubiquitylation through a noncanonical Lys63 chain has been reported, and is required for error-free DNA damage tolerance (or postreplication repair) in yeast. To date, Ubc13 is the only known ubiquitin-conjugating enzyme (Ubc) capable of catalyzing the Lys63-linked polyubiquitylation reaction and this function requires interaction with the Ubc variant Mms2. No information is available on either Lys63-linked ubiquitylation or error-free damage tolerance in plants. We thus cloned and functionally characterized two Arabidopsis thaliana UBC13 genes, AtUBC13A and AtUBC13B. The two genes are highly conserved with respect to chromosomal structure and protein sequence, suggesting that they are derived from a recent gene duplication event. Both AtUbc13 proteins are able to physically interact with yeast or human Mms2, implying that plants also employ the Lys63-linked polyubiquitylation reaction. Furthermore, AtUBC13 genes are able to functionally complement the yeast ubc13 null mutant for spontaneous mutagenesis and sensitivity to DNA damaging agents, suggesting the existence of an error-free DNA damage tolerance pathway in plants. The AtUBC13 genes appear to express ubiquitously and are not induced by various conditions tested.


Subject(s)
Arabidopsis Proteins/genetics , Arabidopsis/genetics , DNA Damage , Polyubiquitin/metabolism , Protein Processing, Post-Translational , Ubiquitin-Conjugating Enzymes/genetics , Amino Acid Sequence , Arabidopsis/metabolism , Arabidopsis Proteins/chemistry , Arabidopsis Proteins/metabolism , Cloning, Molecular , Conserved Sequence , Fungal Proteins/genetics , Fungal Proteins/metabolism , Gene Duplication , Genetic Complementation Test , Humans , Ligases/metabolism , Lysine/chemistry , Molecular Sequence Data , Sequence Alignment , Ubiquitin-Conjugating Enzymes/chemistry , Ubiquitin-Conjugating Enzymes/metabolism , Yeasts/genetics , Yeasts/metabolism
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