BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer
Karachaliou, Niki (Hospital Universitari Quiron Dexeus (Barcelona, Catalunya))
Codony-Servat, Jordi (Pangaea Biotech (Barcelona, Catalunya))
Teixidó, Cristina (Pangaea Biotech (Barcelona, Catalunya))
Pilotto, Sara (University of Verona (Itàlia))
Drozdowskyj, Ana (Pivotal (Madrid))
Codony Servat, Carles (Pangaea Biotech (Barcelona, Catalunya))
Giménez-Capitán, Ana (Pangaea Biotech (Barcelona, Catalunya))
Molina-Vila, Miguel Ángel (Pangaea Biotech (Barcelona, Catalunya))
Bertrán-Alamillo, Jordi (Pangaea Biotech (Barcelona, Catalunya))
Gervais, Radj (Centre François Baclesse (Caen, França))
Massuti, Bartomeu (Hospital General Universitario de Alicante (Alacant, País Valencià))
Morán, Teresa (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Majem, Margarita (Institut d'Investigació Biomèdica Sant Pau)
Felip, Enriqueta (Hospital Universitari Vall d'Hebron)
Carcereny, Enric (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
García-Campelo, Rosario (Complejo Hospitalario Universitario de A Coruña)
Viteri, Santiago (Hospital Universitari Quiron Dexeus (Barcelona, Catalunya))
González-Cao, María (Hospital Universitari Quiron Dexeus (Barcelona, Catalunya))
Morales-Espinosa, Daniela (Hospital Universitari Quiron Dexeus (Barcelona, Catalunya))
Verlicchi, Alberto (Ospedale Santa Maria delle Croci (Ravenna, Itàlia))
Crisetti, Elisabetta (Institute of Respiratory Diseases. University of Foggia (Itàlia))
Chaib, Imane (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Santarpia, Mariacarmela (Human Pathology Department. University of Messina (Itàlia))
Ramirez, Jose Luis (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Bosch-Barrera, J (Hospital Universitari de Girona Doctor Josep Trueta)
Cardona Zorrilla, Andrés Felipe (Instituto de Oncología de Clínica del Country (Bogotá, Colòmbia))
De Marinis, Filippo (Istituto Europeo di Oncologia (Milà, Itàlia))
López-Vivanco, Guillermo (Hospital Universitario de Cruces (Barakaldo, País Basc))
Sánchez, José Miguel (Hospital Universitario de la Princesa (Madrid))
Vergnenegre, Alain (Hôpital du Cluzeau (Limoges, França))
Sánchez Hernández, José Javier (Universidad Autónoma de Nuevo León (Mèxic))
Sperduti, Isabella (Istituto Regina Elena Cancer Institute (Roma, Itàlia))
Bria, Emilio (University of Verona (Itàlia))
Rosell, Rafael (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)

Date:	2015
Abstract:	Abstract. 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.
Note:	Altres ajuts: Fellowship Award of the International Association for the Study of Lung Cancer i grant of the Italian Association for Cancer Research (AIRC My First AIRC Grant n° 14282).
Note:	Altres ajuts: RTICC/RD12/0036/0072
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Non-small-cell lung cancer ; Tumour biomarkers
Published in:	Scientific reports, Vol. 7 (December 2015) , ISSN 2045-2322

DOI: 10.1038/srep17499
PMID: 26639561

12 p, 942.4 KB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles