title: Combination with γ-secretase inhibitor prolongs treatment efficacy of BRAF inhibitor in BRAF-mutated melanoma cells.
abstract: Oncogenic triggering of the MAPK pathway in melanocytes results in senescence, and senescence escape is considered as one critical step for melanocytic transformation. In melanoma, induction of a senescent-like state by BRAF-inhibitors (BRAFi) in a fraction of treated cells - instead of killing - contributes to the repression of tumor growth, but may also provide a source for relapse. Here, we demonstrate that NOTCH activation in melanocytes is not only growth-promoting but it also protects these cells against oncogene-induced senescence. In turn, treatment of melanoma cells with an inhibitor of the NOTCH-activating enzyme γ-secretase led to induction of a senescent-like status in a fraction of the cells but overall achieved only a moderate inhibition of melanoma cell growth. However, combination of γ-secretase inhibitor (GSI) with BRAFi markedly increased the treatment efficacy particularly in long-term culture. Moreover, even melanoma cells starting to regrow after continuous BRAFi treatment - the major problem of BRAFi therapy in patients - can still be affected by the combination treatment. Thus, combining GSI with BRAFi increases the therapeutic efficacy by, at least partially, prolonging the senescent-like state of treated cells.
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Guannan
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Yi
authors.affiliation: Department of Dermatology, University of Regensburg, Regensburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Haferkamp
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hesbacher
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Goebeler
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: gaotw@fmmu.edu.cn.
authors.forename: Tianwen
authors.initials: T
authors.lastname: Gao
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Houben
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Würzburg, Germany. Electronic address: schrama_d@ukw.de.
authors.forename: David
authors.initials: D
authors.lastname: Schrama
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008544:Melanocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D014162:Transfection
chemical_list: C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D051881:Receptor, Notch1; D016160:Retinoblastoma Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D053829:Amyloid Precursor Protein Secretases
keywords: BRAF inhibition; Melanoma; Notch; Senescence