BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer.

Autor:	Karachaliou N; Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain., Codony-Servat J; Pangaea Biotech, Barcelona, Spain., Teixidó C; Pangaea Biotech, Barcelona, Spain., Pilotto S; Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy., Drozdowskyj A; Pivotal, Madrid, Spain., Codony-Servat C; Pangaea Biotech, Barcelona, Spain., Giménez-Capitán A; Pangaea Biotech, Barcelona, Spain., Molina-Vila MA; Pangaea Biotech, Barcelona, Spain., Bertrán-Alamillo J; Pangaea Biotech, Barcelona, Spain., Gervais R; Centre François Baclesse, Caen, France., Massuti B; Hospital General de Alicante, Alicante, Spain., Morán T; Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain., Majem M; Hospital de Sant Pau, Barcelona, Spain., Felip E; Hospital Vall d'Hebron, Barcelona, Spain., Carcereny E; Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain., García-Campelo R; Complexo Hospitalario Universitario La Coruña, Spain., Viteri S; Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain., González-Cao M; Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain., Morales-Espinosa D; Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain., Verlicchi A; Ospedale Santa Maria delle Croci, Ravenna, Italy., Crisetti E; Department of Medical and Surgical Sciences, Institute of Respiratory Diseases, University of Foggia, Italy., Chaib I; Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain., Santarpia M; Medical Oncology Unit, Human Pathology Department, University of Messina, Italy., Luis Ramírez J; Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain., Bosch-Barrera J; Catalan Institute of Oncology, Hospital Josep Trueta, Girona, Spain., Felipe Cardona A; Clinical and Traslational Oncology Group, Institute of Oncology, Clínica del Country, Bogotá, Colombia., de Marinis F; Direttore, Divisione di Oncologica Toracica, Istituto Europeo di Oncologia-IEO, Milano, Italy., López-Vivanco G; Chief, Medical Oncology Service, Hospital de Cruces, Barakaldo, Vizcaya, Spain., Miguel Sánchez J; Medical Oncology Service, Hospital de la Princesa, Madrid, Spain., Vergnenegre A; Hôpital du Cluzeau, Limoges, France., Sánchez Hernández JJ; Unidad de Investigación en Salud Pública CIDICS-UANL., Sperduti I; Biostatistics, Regina Elena National Cancer Institute, Rome., Bria E; Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy., Rosell R; Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain.; Pangaea Biotech, Barcelona, Spain.; Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.; Molecular Oncology Research (MORe) Foundation, Barcelona, Spain.; Germans Trias i Pujol Health Sciences Institute and Hospital, Campus Can Ruti.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2015 Dec 07; Vol. 5, pp. 17499. Date of Electronic Publication: 2015 Dec 07.
DOI:	10.1038/srep17499
Abstrakt:	BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR.
Databáze:	MEDLINE
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