title: PTEN regulates IGF-1R-mediated therapy resistance in melanoma.
abstract: Inhibition of the mitogen-activated protein kinase (MAPK) pathway is a major advance in the treatment of metastatic melanoma. However, its therapeutic success is limited by the rapid emergence of drug resistance. The insulin-like growth factor-1 receptor (IGF-1R) is overexpressed in melanomas developing resistance toward the BRAF(V) (600) inhibitor vemurafenib. Here, we show that hyperactivation of BRAF enhances IGF-1R expression. In addition, the phosphatase activity of PTEN as well as heterocellular contact to stromal cells increases IGF-1R expression in melanoma cells and enhances resistance to vemurafenib. Interestingly, PTEN-negative melanoma cells escape IGF-1R blockade by decreased expression of the receptor, implicating that only in melanoma patients with PTEN-positive tumors treatment with IGF-1R inhibitors would be a suitable strategy to combat therapy resistance. Our data emphasize the crosstalk and therapeutic relevance of microenvironmental and tumor cell-autonomous mechanisms in regulating IGF-1R expression and by this sensitivity toward targeted therapies.
authors.affiliation: Division of Dermatooncology, Department of Dermatology, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Dermatooncology, Department of Dermatology, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Sinnberg
authors.affiliation: Division of Dermatooncology, Department of Dermatology, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Niessner
authors.affiliation: Division of Dermatooncology, Department of Dermatology, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dölker
authors.affiliation: Division of Dermatooncology, Department of Dermatology, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Sauer
authors.affiliation: Division of Dermatooncology, Department of Dermatology, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Kempf
authors.affiliation: Division of Dermatooncology, Department of Dermatology, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Friedegund
authors.initials: F
authors.lastname: Meier
authors.affiliation: Heriot-Watt University, Edinburgh, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Leslie
authors.affiliation: Division of Dermatooncology, Department of Dermatology, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schittek
mesh_terms: D017209:Apoptosis; D002450:Cell Communication; D045744:Cell Line, Tumor; D002470:Cell Survival; D018920:Coculture Techniques; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008545:Melanoma / Q000378:metabolism* / Q000628:therapy; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000628:therapy; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D013449:Sulfonamides; D049452:Green Fluorescent Proteins; D000077484:Vemurafenib; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: IGF-1R; PTEN; melanoma; therapy resistance