title: XPF protein levels determine sensitivity of malignant melanoma cells to oxaliplatin chemotherapy: suitability as a biomarker for patient selection.
abstract: As the options for systemic treatment of malignant melanoma (MM) increase, the need to develop biomarkers to identify patients who might benefit from cytotoxic chemotherapy becomes more apparent. In preclinical models, oxaliplatin has activity in cisplatin-resistant cells. In this study, we have shown that oxaliplatin forms interstrand crosslinks (ICLs) in cellular DNA and that loss of the heterodimeric structure-specific endonuclease XPF-ERCC1 causes hypersensitivity to oxaliplatin in mammalian cells. XPF deficiency resulted in late S-phase arrest and persistence of double-strand breaks following oxaliplatin treatment. In a panel of 12 MM cell lines, oxaliplatin sensitivity correlated with XPF and ERCC1 protein levels. The knockdown of ERCC1 and XPF protein levels by RNA interference increased sensitivity of cancer cells to oxaliplatin; overexpression of exogenous ERCC1 significantly decreased drug sensitivity. Following immunohistochemical optimization, XPF protein levels were quantified in MM tissue samples from 183 patients, showing variation in expression and no correlation with prognosis. In 57 patients with MM treated with cisplatin or carboplatin, XPF protein levels did not predict the likelihood of clinical response. We propose that oxaliplatin should not be discarded as a potential treatment for MM on the basis of the limited activity of cisplatin in unselected patients. Moreover, we show that XPF-ERCC1 protein levels are a key determinant of the sensitivity of melanoma cells to oxaliplatin in vitro. Immunohistochemical detection of XPF appears suitable for development as a tissue biomarker for potentially selecting patients for oxaliplatin treatment in a prospective clinical trial.
authors: Department of Oncology, Oxford NIHR Biomedical Research Centre, Cancer Research UK-Medical Research Council Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford, Oxfordshire, OX3 7DQ, United Kingdom.
authors: Stephanie B
authors: SB
authors: Hatch
authors: Lonnie P
authors: LP
authors: Swift
authors: Simona
authors: S
authors: Caporali
authors: Rebecca
authors: R
authors: Carter
authors: Esme J
authors: EJ
authors: Hill
authors: Thomas P
authors: TP
authors: MacGregor
authors: Stefania
authors: S
authors: D'Atri
authors: Mark R
authors: MR
authors: Middleton
authors: Peter J
authors: PJ
authors: McHugh
authors: Ricky A
authors: RA
authors: Sharma
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015331:Cohort Studies; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D018579:Patient Selection; D016196:S Phase / Q000187:drug effects; D012878:Skin Neoplasms; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000096142:Cutaneous Malignant Melanoma
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D014157:Transcription Factors; C071030:XPF-1 protein, human; D000077150:Oxaliplatin; C071447:ERCC1 protein, human; D004720:Endonucleases
keywords: DNA repair; cell cycle; cytotoxic chemotherapy; tissue biomarker
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