title: Cancer resistance to therapies against the EGFR-RAS-RAF pathway: The role of MEK.
abstract: The mitogen-activated protein kinases (MAPKs) mediate intracellular signals activated by a wide variety of extracellular stimuli. The activation of the RAS-RAF-MEK-MAPK cascade culminates in the regulation of gene transcription promoting cancer cell proliferation, survival, migration and angiogenesis. MEK (mitogen-activated protein kinase kinase-MAPKK) 1/2 is a transducer of the growth factor receptor-RAS-RAF-MAPK signalling cascade and plays a relevant role in development and progression of human cancers, such as colorectal cancer (CRC), non small cell lung cancer (NSCLC). Direct inhibition of MEK is a promising strategy and several inhibitors are currently under evaluation in clinical trials showing initial clinical activity in different tumours. MEK activation, by different genetic mechanisms, has been described for both intrinsic and acquired resistance to drugs targeting the EGFR (Epidermal Growth Factor Receptor)-RAS-RAF pathway in CRC, NSCLC. Combination therapies with chemotherapy and/or with molecular targeted agents are warranted and biomarkers studies are needed to identify those tumours dependent on MEK signalling.
authors.affiliation: Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Università degli Studi della Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Napoli, Italy. Electronic address: erika.martinelli@unina2.it.
authors.forename: Erika
authors.initials: E
authors.lastname: Martinelli
authors.affiliation: Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Università degli Studi della Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Morgillo
authors.affiliation: Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Università degli Studi della Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Troiani
authors.affiliation: Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Università degli Studi della Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C482128:MAP2K2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D018631:ras Proteins
keywords: CRC; MEK; NSCLC; Resistance