title: Receptor tyrosine kinase inhibitors and cytotoxic drugs affect pleural mesothelioma cell proliferation: insight into EGFR and ERK1/2 as antitumor targets.
abstract: Malignant pleural mesothelioma (MPM) is an aggressive chemotherapy-resistant cancer. Up-regulation of epidermal growth factor receptor (EGFR) plays an important role in MPM development and EGFR-tyrosine kinase inhibitors (TKIs) may represent novel therapeutic options. We tested the effects of the EGFR TKIs gefitinib and erlotinib and TKIs targeted to other growth factors (VEGFR and PDGFR), in comparison to standard antineoplastic agents, in two human MPM cell lines, IST-Mes2 and ZL55. All drugs showed IC(50) values in the micromolar range: TKIs induced cytostatic effects at concentrations up to the IC(50,) while conventional drug growth-inhibitory activity was mainly cytotoxic. Moreover, the treatment of IST-Mes2 with TKIs (gefitinib and imatinib mesylate) in combination with cisplatin and gemcitabine did not show additivity. Focusing on the molecular mechanisms underlying the antiproliferative and pro-apoptotic effects of EGFR-TKIs, we observed that gefitinib induced the formation and stabilization of inactive EGFR homodimers, even in absence of EGF, as demonstrated by EGFR B(max) and number of sites/cell. The analysis of downstream effectors of EGFR signaling demonstrated that EGF-induced proliferation, reverted by gefitinib, involved ERK1/2 activation, independently from Akt pathway. Gefitinib inhibits MPM cell growth and survival, preventing EGF-dependent activation of ERK1/2 pathway by blocking EGFR-TK phosphorylation and stabilizing inactive EGFR dimers. Along with the molecular definition of TKIs pharmacological efficacy in vitro, these results may contribute to delve deep into the promising but still controversial role for targeted and conventional drugs in the therapy of MPM.
authors.affiliation: Laboratory of Pharmacology, Department of Oncology, Biology and Genetics, University of Genova, Viale Benedetto XV, 2-16132 Genova, Italy. federica.barbieri@unige.it
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
authors.forename: Roberto
authors.initials: R
authors.lastname: Würth
authors.forename: Roberto E
authors.initials: RE
authors.lastname: Favoni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pattarozzi
authors.forename: Monica
authors.initials: M
authors.lastname: Gatti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ratto
authors.forename: Angelo
authors.initials: A
authors.lastname: Ferrari
authors.forename: Adriana
authors.initials: A
authors.lastname: Bajetto
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases