title: A Nexus Consisting of Beta-Catenin and Stat3 Attenuates BRAF Inhibitor Efficacy and Mediates Acquired Resistance to Vemurafenib.
abstract: Acquired resistance to second generation BRAF inhibitors (BRAFis), like vemurafenib is limiting the benefits of long term targeted therapy for patients with malignant melanomas that harbor BRAF V600 mutations. Since many resistance mechanisms have been described, most of them causing a hyperactivation of the MAPK- or PI3K/AKT signaling pathways, one potential strategy to overcome BRAFi resistance in melanoma cells would be to target important common signaling nodes. Known factors that cause secondary resistance include the overexpression of receptor tyrosine kinases (RTKs), alternative splicing of BRAF or the occurrence of novel mutations in MEK1 or NRAS. In this study we show that β-catenin is stabilized and translocated to the nucleus in approximately half of the melanomas that were analyzed and which developed secondary resistance towards BRAFi. We further demonstrate that β-catenin is involved in the mediation of resistance towards vemurafenib in vitro and in vivo. Unexpectedly, β-catenin acts mainly independent of the TCF/LEF dependent canonical Wnt-signaling pathway in resistance development, which partly explains previous contradictory results about the role of β-catenin in melanoma progression and therapy resistance. We further demonstrate that β-catenin interacts with Stat3 after chronic vemurafenib treatment and both together cooperate in the acquisition and maintenance of resistance towards BRAFi.
authors.affiliation: Department of Dermatology, Division of Dermatooncology, Eberhard-Karls-University Tübingen, Germany. Electronic address: tobias.sinnberg@med.uni-tuebingen.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Sinnberg
authors.affiliation: Department of Dermatology, Division of Dermatooncology, Eberhard-Karls-University Tübingen, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Makino
authors.affiliation: Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard-Karls-University Tübingen, Germany.
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Krueger
authors.affiliation: Proteome Center Tübingen, Eberhard-Karls-University Tübingen, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Velic
authors.affiliation: Proteome Center Tübingen, Eberhard-Karls-University Tübingen, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Macek
authors.affiliation: NMI Natural and Medical Sciences Institute at the University Tübingen, Reutlingen, Germany; Pharmaceutical Biotechnology, Eberhard-Karls University Tübingen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rothbauer
authors.affiliation: NMI Natural and Medical Sciences Institute at the University Tübingen, Reutlingen, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Groll
authors.affiliation: NMI Natural and Medical Sciences Institute at the University Tübingen, Reutlingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Pötz
authors.affiliation: Quantitative Biology Center (QBiC), Eberhard-Karls-University Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Czemmel
authors.affiliation: Department of Dermatology, Division of Dermatooncology, Eberhard-Karls-University Tübingen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Niessner
authors.affiliation: Department of Dermatology, Division of Dermatooncology, Eberhard-Karls-University Tübingen, Germany; Department of Dermatology, Carl Gustav Carus Medical Center, TU Dresden, Germany.
authors.forename: Friedegund
authors.initials: F
authors.lastname: Meier
authors.affiliation: Department of Pathology, University Hospital of Zürich, Zürich, Switzerland.
authors.forename: Kristian
authors.initials: K
authors.lastname: Ikenberg
authors.affiliation: Department of Dermatology, Division of Dermatooncology, Eberhard-Karls-University Tübingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.affiliation: Department of Dermatology, Division of Dermatooncology, Eberhard-Karls-University Tübingen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schittek
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D019279:Resin Cements; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C433206:Nexus; D047428:Protein Kinase Inhibitors; D019279:Resin Cements; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D051176:beta Catenin; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; Melanoma; Resistance; Stat3; Vemurafenib; β-catenin