title: Signaling intermediates (MAPK and PI3K) as therapeutic targets in NSCLC.
abstract: The RAS/RAF/MEK/ ERK and the PI3K/AKT/mTOR pathways govern fundamental physiological processes, such as cell proliferation, differentiation, metabolism, cytoskeleton reorganization and cell death and survival. Constitutive activation of these signal transduction pathways is a required hallmark of cancer and dysregulation, on either genetic or epigenetic grounds, of these pathways has been implicated in the initiation, progression and metastastic spread of lung cances. Targeting components of the MAPK and PI3K cascades is thus an attractive strategy in the development of novel therapeutic approaches to treat lung cancer, although the use of single pathway inhibitors has met with limited clinical success so far. Indeed, the presence of intra- and inter-pathway compensatory loops that re-activate the very same cascade, either upstream or downstream the point of pharmacological blockade, or activate the alternate pathway following the blockade of one signaling cascade has been demonstrated, potentially driving preclinical (and possibly clinical) resistance. Therefore, the blockade of both pathways with combinations of signaling inhibitors might result in a more efficient anti-tumor effect, and thus potentially overcome and/or delay clinical resistance, as compared with single agent. The current review aims at summarizing the current status of preclinical and clinical research with regard to pathway crosstalks between the MAPK and PI3K cascades in NSCLC and the rationale for combined therapeutic pathway targeting.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Ciuffreda
authors.forename: Ursula Cesta
authors.initials: UC
authors.lastname: Incani
authors.forename: Linda S
authors.initials: LS
authors.lastname: Steelman
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Abrams
authors.forename: Italia
authors.initials: I
authors.lastname: Falcone
authors.forename: Anais Del
authors.initials: AD
authors.lastname: Curatolo
authors.forename: William H
authors.initials: WH
authors.lastname: Chappell
authors.forename: Richard A
authors.initials: RA
authors.lastname: Franklin
authors.forename: Sabrina
authors.initials: S
authors.lastname: Vari
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. michelemilella@hotmail.com.
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors