title: Uncoupling of the epidermal growth factor receptor from downstream signal transduction molecules guides the acquired resistance to gefitinib in prostate cancer cells.
abstract: The clinical efficacy of ErbB1 kinase inhibitors is limited by the development of acquired autoresistance. The activation of alternative signaling pathways can contribute to gefitinib resistance. In this study, we demonstrate that the continuous in vitro exposure of the phosphatase and tensin homologue (deleted from chromosome 10)-negative prostate cancer (PC)3 cell line to gefitinib resulted in a sustained growth inhibition of 50% for about 2 months, but afterwards the surviving cells resumed their usual proliferation rate. During chronic treatment, gefitinib-treated cells developed drug resistance undergoing a G0/G1 cell cycle arrest, with a corresponding reduction in the G2/M cells without evident cell apoptosis, and thus a tyrosine kinase inhibitor-resistant (TKI-R) PC3 cell subline was isolated. TKI-R cells show i) an increment in basal ERK activation, ii) an epidermal growth factor-mediated and gefitinib insensitive ERK phosporylation, iii) increased levels of Her2/Neu, iv) a significant decrement in epidermal growth factor receptor (EGFR) expression, v) a very low sensitivity against EGFR TKIs and blocking antibodies, vi) a moderate increase in the sensitivity to growth inhibition by the Her2 inhibitor, AG825 or by 2C4, the humanized monoclonal antibody which blocks Her2 heterodymerization, vii) an increased expression of the neutrophine receptors, TrkA and TrkB, and viii) a significantly increased sensitivity to growth inhibition by the TrkA inhibitor, CEP701. Treatment with a mitogen-activated-protein kinase inhibitor abolished gefitinib resistance completely. Therefore, the ability of tumor cells to maintain high ERK activity under EGFR inhibition could represent a potential mechanism of the resistance to gefitinib.
authors.affiliation: Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy. festucci@univaq.it
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Gravina
authors.forename: Danilo
authors.initials: D
authors.lastname: Millimaggi
authors.forename: Paola
authors.initials: P
authors.lastname: Muzi
authors.forename: Silvia
authors.initials: S
authors.lastname: Speca
authors.forename: Enrico
authors.initials: E
authors.lastname: Ricevuto
authors.forename: Carlo
authors.initials: C
authors.lastname: Vicentini
authors.forename: Mauro
authors.initials: M
authors.lastname: Bologna
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D008297:Male; D020932:Nerve Growth Factor / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib; D020932:Nerve Growth Factor; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB; C485206:pertuzumab