title: Computational Modeling of PI3K/AKT and MAPK Signaling Pathways in Melanoma Cancer.
abstract: BACKGROUND
  Malignant melanoma is an aggressive tumor of the skin and seems to be resistant to current therapeutic approaches. Melanocytic transformation is thought to occur by sequential accumulation of genetic and molecular alterations able to activate the Ras/Raf/MEK/ERK (MAPK) and/or the PI3K/AKT (AKT) signalling pathways. Specifically, mutations of B-RAF activate MAPK pathway resulting in cell cycle progression and apoptosis prevention. According to these findings, MAPK and AKT pathways may represent promising therapeutic targets for an otherwise devastating disease.
  
  
  RESULTS
  Here we show a computational model able to simulate the main biochemical and metabolic interactions in the PI3K/AKT and MAPK pathways potentially involved in melanoma development. Overall, this computational approach may accelerate the drug discovery process and encourages the identification of novel pathway activators with consequent development of novel antioncogenic compounds to overcome tumor cell resistance to conventional therapeutic agents. The source code of the various versions of the model are available as S1 Archive.
authors.affiliation: Department of Drug Sciences, University of Catania, 95125, Catania, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pappalardo
authors.affiliation: Department of Drug Sciences, University of Catania, 95125, Catania, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Russo
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, 95125, Catania, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Candido
authors.affiliation: Department of Mathematics and Computer Science, University of Catania, 95125, Catania, Italy.
authors.forename: Marzio
authors.initials: M
authors.lastname: Pennisi
authors.affiliation: Department of Engineering, University of Catania, 95125, Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cavalieri
authors.affiliation: Department of Mathematics and Computer Science, University of Catania, 95125, Catania, Italy.
authors.forename: Santo
authors.initials: S
authors.lastname: Motta
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, United States of America.
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, 95125, Catania, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, 95125, Catania, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003198:Computer Simulation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000378:metabolism*; D009154:Mutation; D010091:Oximes / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism*; D000096142:Cutaneous Malignant Melanoma
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; D019869:Phosphatidylinositol 3-Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib