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
VOLUME: 19 ISSUE: 5
Author(s):Elena Galvani, Roberta Alfieri, Elisa Giovannetti, Andrea Cavazzoni, Silvia La Monica, Maricla Galetti, Claudia Fumarola, Mara Bonelli, Marco Mor, Marcello Tiseo, Godefridus J. Peters, Pier Giorgio Petronini and Andrea Ardizzoni
Affiliation:Department of Clinical and Experimental Medicine, University of Parma, Via Gramsci 14, 43126 Parma, Italy.
Keywords:EGFR, NSCLC, tyrosine kinase, gefitinib, erlotinib, acquired resistance, therapy, solid tumors, cancer, biomarkers
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.
