title: Erlotinib: preclinical investigations.
abstract: Erlotinib (Tarceva) is an orally available selective small-molecule inhibitor of HER1/EGFR tyrosine kinase with a 50% inhibitory concentration of 2 nM for purified tyrosine kinase. This agent has been shown to produce stasis or regression of tumor growth in human cancer xenograft models, including non-small-cell lung cancer models. Ongoing preclinical investigations indicate that inhibition of the MAPK and Atk signaling pathways downstream of HER1/EGFR may be required for optimal antitumor effects. Erlotinib exhibits inhibition of MAPK and Atk kinases at concentrations higher than those required for HER1/EGFR tyrosine kinase inhibition; such findings suggest that maximal inhibition of HER1/EGFR, requiring high erlotinib doses, is necessary for optimum antitumor activity. These considerations are supported by tumor models, including non-small-cell lung cancer models, showing dose-related antitumor effects up to high doses of erlotinib. Erlotinib exhibits additive antitumor effects when combined with chemotherapeutic agents (cisplatin, doxorubicin, paclitaxel, gemcitabine [Gemzar], and capecitabine [Xeloda]), radiation therapy, and other targeted agents (e.g., bevacizumab [Avastin]). Recent studies indicate that erlotinib inhibits the EGFRvIII mutant at concentrations higher than those required for inhibition of wild-type receptor. Ongoing investigation will help to determine optimal dosing and dose frequency of erlotinib in various cancers in the clinical setting.
authors.affiliation: Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000503:physiopathology; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D020929:Mitogen-Activated Protein Kinase Kinases