title: The CSPG4-specific monoclonal antibody enhances and prolongs the effects of the BRAF inhibitor in melanoma cells.
abstract: PLX4032 is a BRAF-selective inhibitor shown to be efficacious in the treatment of melanomas presenting with the BRAF(V600E) mutation. However, favorable responses to treatment are short-lived, and complete remission is rarely observed. Therefore, it is important to identify novel therapies designed to enhance treatment responses and to increase the longevity of initial response to BRAF inhibitors. To this end, we characterized the effects of the 225.28 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibody (mAb) capable of blocking multiple signaling pathways important to cell growth, migration, and survival. Addition of 225.28 to the treatment regimen enhanced the in vitro response magnitude and the duration efficacy of PLX4032 in treating CSPG4(+), BRAF(V600E) melanoma cells (melanoma(BRAF(V600E)/CSPG4+) cells). Data presented in this report demonstrated that (1) treatments comprised of PLX4032 and mAb 225.28 were more effective at inhibiting melanoma(BRAF(V600E)/CSPG4+) cell growth than either agent alone, (2) mAb 225.28 prevented/delayed the development of resistance in melanoma(BRAF(V600E)/CSPG4+) cells to PLX4032, and (3) the mechanism of action of the combination therapy caused a down-regulation in multiple signaling pathways. This study provides a foundation for future investigations designed to improve BRAF inhibitor effectiveness in vitro and in vivo for treating melanoma(BRAF(V600E)/CSPG4+) cells in combination with a CSPG4-specific mAb.
authors: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15232, USA.
authors: Ling
authors: L
authors: Yu
authors: Elvira
authors: E
authors: Favoino
authors: Yangyang
authors: Y
authors: Wang
authors: Yang
authors: Y
authors: Ma
authors: Xiaojuan
authors: X
authors: Deng
authors: Xinhui
authors: X
authors: Wang
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D011508:Chondroitin Sulfate Proteoglycans / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000276:immunology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000911:Antibodies, Monoclonal; D011508:Chondroitin Sulfate Proteoglycans; D007211:Indoles; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D013449:Sulfonamides; D000077484:Vemurafenib; C101390:CSPG4 protein, human; D000099216:Chondroitin Sulfate Proteoglycan 4; C482119:BRAF protein, human