title: [Mechanism of action and preclinical development of afatinib].
abstract: Afatinib, together with gefitinib and erlotinib, is approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). This is an irreversible inhibitor of the ErbB family, acting on EGFR (HER1, ErbB1), ErbB2 (HER2) and ErbB4 (HER4). Covalent attachment to cysteine residues in the catalytic domain of EGFR, HER2 and ErbB4 inhibits the tyrosine kinase activity (TKIs) of these receptors, decreasing auto- and transphosphorylation between ErbB dimers, and thus blocking the activity of downstream signalling pathways related to growth and apoptosis suppression. In preclinical models, this has resulted in a reduction in tumour size. Furthermore, due to its mechanism of action, afatinib may be more potent than the first-generation EGFR TKIs (gefitinib and erlotinib) and may even be able to overcome acquired resistance to such treatments. Finally, because of the demonstrated synergism with other chemotherapeutic and target agents, it could be interesting to enhance its clinical development in combination with other drugs.
authors.affiliation: Servicio de Oncología Médica, Complejo Asistencial Universitario de León (CAULE), León, España. Electronic address: pilardiz@tudiscovirtual.com.
authors.forename: Pilar
authors.initials: P
authors.lastname: Diz Taín
authors.affiliation: Servicio de Oncología Médica, Complejo Asistencial Universitario de León (CAULE), León, España.
authors.forename: Ana López
authors.initials: AL
authors.lastname: González
authors.affiliation: Servicio de Oncología Médica, Complejo Asistencial Universitario de León (CAULE), León, España.
authors.forename: Andrés
authors.initials: A
authors.lastname: García-Palomo
mesh_terms: D000077716:Afatinib; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D051381:Rats; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D066246:ErbB Receptors
keywords: Advanced non-small cell lung cancer; Afatinib; Cáncer de pulmón de célula no pequeña; Epidermal growth factor receptor; ErbB family; Erlotinib; Familia ErbB; Gefitinib; Receptor del factor de crecimiento epidérmico; avanzado