title: Evidence for upregulation of Bim and the splicing factor SRp55 in melanoma cells from patients treated with selective BRAF inhibitors.
abstract: Relatively little attention has been paid to the activity of selective BRAF inhibitors in the induction of apoptosis in melanoma, particularly in vivo. In the present study, we have isolated cultures from biopsies taken from four patients before and during the treatment of their melanoma. We report that the cell lines taken during treatment show varying degrees of upregulation of the proapoptotic BH3 protein Bim and its splice forms, downregulation of Mcl-1, and upregulation of the splicing factor SRp55 as reported in previous in-vitro studies. There was also evidence of ongoing apoptotic signaling despite the continued growth of the cultures. The cultures established during the treatment were largely resistant to the selective BRAF inhibitor PLX4720, consistent with the acquired resistance of melanoma in the treated patients. These results provide further insights into the mechanism of action of these agents against melanoma.
authors.affiliation: Oncology & Immunology Unit, Calvary Mater Newcastle Hospital, Royal North Shore Hospital, University of Sydney, New South Wales, Australia.
authors.forename: Fritz
authors.initials: F
authors.lastname: Lai
authors.forename: Chen Chen
authors.initials: CC
authors.lastname: Jiang
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Farrelly
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001706:Biopsy; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010091:Oximes / Q000627:therapeutic use*; D010750:Phosphoproteins / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D007093:Imidazoles; D007211:Indoles; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010091:Oximes; C528407:PLX 4720; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins; C489470:SRSF6 protein, human; D013449:Sulfonamides; D000068103:Serine-Arginine Splicing Factors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C561627:dabrafenib