title: Epidermal growth factor receptor tyrosine kinase inhibitors: current status and future perspectives in the development of novel irreversible inhibitors for the treatment of mutant non-small cell lung cancer.
abstract: Conventional chemotherapeutic regimens have reached an efficacy plateau against most solid tumors and deal with significant toxicity. Recently, the goal of oncologic research to improve outcome and reduce treatment-related side-effects has led to the development of novel anticancer treatments targeting specific proteins or genes involved in cancer growth and progression. In particular, the tyrosine- kinase inhibitors (TKIs) gefitinib and erlotinib targeting the epidermal growth factor receptor (EGFR) have been approved for the treatment of non-small-cell lung cancer (NSCLC). Their clinical activity has been related to different clinical and biological parameters, such as the presence of activating mutations in the kinase domain of the target. Disappointingly, their clinical efficacy is limited by the development of resistance which is caused in more than 50% of the cases by the emergence of a secondary point-mutation (T790M) in the ATP-binding cleft of EGFR. Several novel EGFR inhibitors, able to covalently bind the target and prolong its inactivation, have been developed with the aim to overcome such resistance and are evaluated in ongoing clinical studies. However, not all clinical outcomes, including tolerability, are explained, and the identification/validation of novel biomarkers of sensitivity or resistance to such agents is a viable area of research to improve their clinical use. This review summarizes the current knowledge on the functional role of activating mutations of EGFR, pivotal primary/acquired resistance mechanisms as well as clinical data of small molecule EGFR-TKIs, and discusses the future of such therapeutic approach in NSCLC.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126 Parma, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Galvani
authors.forename: Roberta
authors.initials: R
authors.lastname: Alfieri
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavazzoni
authors.forename: Silvia
authors.initials: S
authors.lastname: La Monica
authors.forename: Maricla
authors.initials: M
authors.lastname: Galetti
authors.forename: Claudia
authors.initials: C
authors.lastname: Fumarola
authors.forename: Mara
authors.initials: M
authors.lastname: Bonelli
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Marcello
authors.initials: M
authors.lastname: Tiseo
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Petronini
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors