title: Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases.
abstract: Brain metastases are the most common cause of death in patients with metastatic melanoma, and the RAF-MEK-ERK and PI3K-AKT signaling pathways are key players in melanoma progression and drug resistance. The BRAF inhibitor vemurafenib significantly improved overall survival. However, brain metastases still limit the effectiveness of this therapy. In a series of patients, we observed that treatment with vemurafenib resulted in substantial regression of extracerebral metastases, but brain metastases developed. This study aimed to identify factors that contribute to treatment resistance in brain metastases. Matched brain and extracerebral metastases from melanoma patients had identical ERK, p-ERK, and AKT immunohistochemistry staining patterns, but there was hyperactivation of AKT (p-AKT) and loss of PTEN expression in the brain metastases. Mutation analysis revealed no differences in BRAF, NRAS, or KIT mutation status in matched brain and extracerebral metastases. In contrast, AKT, p-AKT, and PTEN expression was identical in monolayer cultures derived from melanoma brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness than melanoma cells stimulated by fibroblast-conditioned medium. Inhibition of PI3K-AKT signaling resensitized melanoma cells isolated from a vemurafenib-resistant brain metastasis to vemurafenib. Brain-derived factors appear to induce hyperactivation of the AKT survival pathway and to promote the survival and drug resistance of melanoma cells in the brain. Thus, inhibition of PI3K-AKT signaling shows potential for enhancing and/or prolonging the antitumor effect of BRAF inhibitors or other anticancer agents in melanoma brain metastases.
authors.affiliation: Division of Dermatologic Oncology, Department of Dermatology, University of Tuebingen Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Niessner
authors.forename: Andrea
authors.initials: A
authors.lastname: Forschner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Klumpp
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Honegger
authors.forename: Maria
authors.initials: M
authors.lastname: Witte
authors.forename: Antje
authors.initials: A
authors.lastname: Bornemann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.forename: Annemarie
authors.initials: A
authors.lastname: Adam
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bauer
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Tabatabai
authors.forename: Keith
authors.initials: K
authors.lastname: Flaherty
authors.forename: Tobias
authors.initials: T
authors.lastname: Sinnberg
authors.forename: Daniela
authors.initials: D
authors.lastname: Beck
authors.forename: Ulrike
authors.initials: U
authors.lastname: Leiter
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
authors.forename: Alexander
authors.initials: A
authors.lastname: Roesch
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
authors.forename: Thomas
authors.initials: T
authors.lastname: Eigentler
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kulms
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Friedegund
authors.initials: F
authors.lastname: Meier
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001253:Astrocytes / Q000378:metabolism; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004252:DNA Mutational Analysis / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed; D014407:Tumor Cells, Cultured; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D007211:Indoles; D008565:Membrane Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: AKT; BRAF inhibitors; brain metastasis; melanoma; therapy resistance