title: Drug development to overcome resistance to EGFR inhibitors in lung and colorectal cancer.
abstract: Epidermal growth factor receptor (EGFR) is a validated target in different human malignancies. EGFR tyrosine kinase inhibitors (TKIs) are known to contribute considerably to the extension of progression-free survival in EGFR-mutant non-small cell lung cancer and monoclonal antibodies (mAbs) targeting EGFR have also improved the efficacy outcomes in KRAS wild-type colorectal cancer. Nevertheless, a significant percentage of lung and colorectal cancer patients do not respond to anti-EGFR agents and secondary resistance after initial benefit is a challenging reality faced by clinicians. Extensive preclinical work on the potential mechanisms of resistance to EGFR inhibitors in different disease settings has guided the development of second-generation irreversible EGFR TKIs, more efficient anti-EGFR mAbs, and combination strategies with agents targeting other receptors and downstream effectors. In order to elucidate the role of the multiple therapeutic strategies under investigation to overcome EGFR inhibitors-resistance, rational drug development based on stringent preclinical data, biomarker validation and proper selection of patients in the ongoing clinical trials are of paramount importance. Preliminary results of clinical trials evaluating these approaches will be discussed in this manuscript, with emphasis on TKIs in lung cancer and mAbs in advanced colorectal cancer.
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, P Vall d'Hebron 119-129, 08035 Barcelona, Spain. rdienstmann@vhebron.net
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Dienstmann
authors.forename: Sara
authors.initials: S
authors.lastname: De Dosso
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Felip
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
mesh_terms: D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D055808:Drug Discovery / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors