title: Enhancing the evaluation of PI3K inhibitors through 3D melanoma models.
abstract: Targeted therapies for mutant BRAF metastatic melanoma are effective but not curative due to acquisition of resistance. PI3K signaling is a common mediator of therapy resistance in melanoma; thus, the need for effective PI3K inhibitors is critical. However, testing PI3K inhibitors in adherent cultures is not always reflective of their potential in vivo. To emphasize this, we compared PI3K inhibitors of different specificity in two- and three-dimensional (2D, 3D) melanoma models and show that drug response predictions gain from evaluation using 3D models. Our results in 3D demonstrate the anti-invasive potential of PI3K inhibitors and that drugs such as PX-866 have beneficial activity in physiological models alone and when combined with BRAF inhibition. These assays finally help highlight pathway effectors that could be involved in drug response in different environments (e.g. p4E-BP1). Our findings show the advantages of 3D melanoma models to enhance our understanding of PI3K inhibitors.
authors: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.|Department of Dermatology, University Hospital Essen, Essen, Germany.
authors: Batool
authors: B
authors: Shannan
authors: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors: Quan
authors: Q
authors: Chen
authors: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors: Andrea
authors: A
authors: Watters
authors: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors: Michela
authors: M
authors: Perego
authors: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors: Clemens
authors: C
authors: Krepler
authors: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors: Rakhee
authors: R
authors: Thombre
authors: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors: Ling
authors: L
authors: Li
authors: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors: Geena
authors: G
authors: Rajan
authors: Oncothyreon, Inc., Seattle, WA, USA.
authors: Scott
authors: S
authors: Peterson
authors: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors: Phyllis A
authors: PA
authors: Gimotty
authors: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors: Melissa
authors: M
authors: Wilson
authors: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors: Katherine L
authors: http://orcid.org/0000-0002-6740-0901
authors: KL
authors: Nathanson
authors: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors: Tara C
authors: TC
authors: Gangadhar
authors: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors: Lynn M
authors: LM
authors: Schuchter
authors: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors: Ashani T
authors: AT
authors: Weeraratna
authors: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors: Meenhard
authors: M
authors: Herlyn
authors: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors: Adina
authors: A
authors: Vultur
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology; D006067:Gonanes / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000201:enzymology / Q000473:pathology*; D016688:Mice, Inbred NOD; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D003094:Collagen; D006067:Gonanes; D007211:Indoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; C528407:PLX 4720; C496788:PX-866
keywords: 3D models; PI3K inhibition; PX-866; melanoma; mutant BRAF; resistance