title: Targeted BRAF inhibition impacts survival in melanoma patients with high levels of Wnt/β-catenin signaling.
abstract: Unprecedented clinical responses have been reported in advanced stage metastatic melanoma patients treated with targeted inhibitors of constitutively activated mutant BRAF, which is present in approximately half of all melanomas. We and others have previously observed an association of elevated nuclear β-catenin with improved survival in molecularly-unselected melanoma patients. This study sought to determine whether levels of Wnt/β-catenin signaling in melanoma tumors prior to treatment might predict patient responses to BRAF inhibitors (BRAFi). We performed automated quantification of β-catenin immunohistochemical expression in pretreatment BRAF-mutant tumors from 32 BRAFi-treated melanoma patients. Unexpectedly, patients with higher nuclear β-catenin in their tumors did not exhibit the survival advantage previously observed in molecularly-unselected melanoma patients who did not receive BRAFi. In cultured melanoma cells treated with long-term BRAFi, activation of Wnt/β-catenin signaling is markedly inhibited, coinciding with a loss of the enhancement of BRAFi-induced apoptosis by WNT3A observed in BRAFi-naïve cells. Together, these observations suggest that long-term treatment with BRAFi can impact the interaction between BRAF/MAPK and Wnt/β-catenin signaling to affect patient outcomes. Studies with larger patient cohorts are required to determine whether nuclear β-catenin expression correlates with clinical responses to BRAFi and to specific mechanisms of acquired resistance to BRAFi. Understanding these pathway interactions will be necessary to facilitate efforts to individualize therapies for melanoma patients.
authors.affiliation: Division of Dermatology, University of Washington Department of Medicine, Seattle, Washington, United States of America; The Group Health Research Institute, Seattle, Washington, United States of America.
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Chien
authors.affiliation: Melanoma Institute of Australia, Sydney, New South Wales, Australia; The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Haydu
authors.affiliation: Division of Dermatology, University of Washington Department of Medicine, Seattle, Washington, United States of America.
authors.forename: Travis L
authors.initials: TL
authors.lastname: Biechele
authors.affiliation: Division of Dermatology, University of Washington Department of Medicine, Seattle, Washington, United States of America.
authors.forename: Rima M
authors.initials: RM
authors.lastname: Kulikauskas
authors.affiliation: Melanoma Institute of Australia, Sydney, New South Wales, Australia; The University of Sydney, Sydney, New South Wales, Australia; Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
authors.affiliation: Melanoma Institute of Australia, Sydney, New South Wales, Australia; The University of Sydney, Sydney, New South Wales, Australia; Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead, New South Wales, Australia; Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: Melanoma Institute of Australia, Sydney, New South Wales, Australia; The University of Sydney, Sydney, New South Wales, Australia; Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: The Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America.
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.affiliation: Melanoma Institute of Australia, Sydney, New South Wales, Australia; The University of Sydney, Sydney, New South Wales, Australia; Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead, New South Wales, Australia; Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008544:Melanocytes / Q000201:enzymology; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D016896:Treatment Outcome; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism*; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases
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