title: Effects of BRAF inhibitors on human melanoma tissue before treatment, early during treatment, and on progression.
abstract: Selective BRAF inhibitors (BRAFi) are a standard of care for the treatment of BRAF(V) (600) -mutant metastatic melanoma. We analyzed a unique set of serial triplicate human metastatic melanoma tumor biopsies to identify biomarkers of BRAFi response and resistance. Morphologic features and immunohistochemical biomarkers were analyzed in 37 metastatic melanoma biopsies at pretreatment (PRE), early during treatment (EDT), and on progression (PROG) from 15 patients treated with a BRAFi and correlated with response and outcome. At EDT, proliferative markers decreased regardless of response, whereas markers of cell death increased in responders. High expression of nuclear p27 at baseline was the strongest predictor of a poorer OS and predicted worse response. The results show that BRAFi are universally antiproliferative, regardless of clinical response, whereas markers of cell death increased only in responders. The addition of therapies targeting the cell cycle machinery may improve the response and duration of BRAFi, and investigation of the mechanisms of apoptosis may provide additional therapeutic targets.
authors.affiliation: Melanoma Institute Australia, Sydney, NSW, Australia. georgina.long@sydney.edu.au
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Haydu
authors.forename: Varsha
authors.initials: V
authors.lastname: Tembe
authors.forename: Raghwa
authors.initials: R
authors.lastname: Sharma
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Julie
authors.initials: J
authors.lastname: Howle
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D049109:Cell Proliferation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010091:Oximes / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology; D016896:Treatment Outcome; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib