title: MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines.
abstract: Elevated activity of the mitogen-activated protein kinase (MAPK) signaling cascade is found in the majority of human melanomas and is known to regulate proliferation, survival and invasion. Current targeted therapies focus on decreasing the activity of this pathway; however, we do not fully understand how these therapies impact tumor biology, especially given that melanoma is a heterogeneous disease. Using a three-dimensional (3D), collagen-embedded spheroid melanoma model, we observed that MEK and BRAF inhibitors can increase the invasive potential of ∼20% of human melanoma cell lines. The invasive cell lines displayed increased receptor tyrosine kinase (RTK) activity and activation of the Src/FAK/signal transducers and activators of transcription-3 (STAT3) signaling axis, also associated with increased cell-to-cell adhesion and cadherin engagement following MEK inhibition. Targeting various RTKs, Src, FAK and STAT3 with small molecule inhibitors in combination with a MEK inhibitor prevented the invasive phenotype, but only STAT3 inhibition caused cell death in the 3D context. We further show that STAT3 signaling is induced in BRAF-inhibitor-resistant cells. Our findings suggest that MEK and BRAF inhibitors can induce STAT3 signaling, causing potential adverse effects such as increased invasion. We also provide the rationale for the combined targeting of the MAPK pathway along with inhibitors of RTKs, SRC or STAT3 to counteract STAT3-mediated resistance phenotypes.
authors.affiliation: Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Vultur
authors.affiliation: Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Villanueva
authors.affiliation: Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Krepler
authors.affiliation: Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Rajan
authors.affiliation: Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Gimotty
authors.affiliation: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Imaging Facility, Division of Molecular and Cellular Biology, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hayden
authors.affiliation: Imaging Facility, Division of Molecular and Cellular Biology, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Keeney
authors.affiliation: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: 1] Molecular and Cellular Oncogenesis Program, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA [2] Imaging Facility, Division of Molecular and Cellular Biology, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Herlyn
mesh_terms: D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002470:Cell Survival; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism*
chemical_list: D015820:Cadherins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases