Journal Article

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

Gervais, Radj, Verlicchi, Alberto, Luis Ramírez, José, de Marinis, Filippo, Drozdowskyj, Ana, Karachaliou, Niki, Bertrán-Alamillo, Jordi, Sánchez Hernández, José Javier, Majem, Margarita, Chaib, Imane, Santarpia, Mariacarmela, Bria, Emilio, Codony-Servat, Carles, Teixidó, Cristina, González-Cao, María, Vergnenegre, Alain, Giménez-Capitán, Ana, Codony-Servat, Jordi, Miguel Sánchez, José, Pilotto, Sara, López-Vivanco, Guillermo, Massuti, Bartomeu, Felip, Enriqueta, Viteri, Santiago, García-Campelo, Rosario, Morán, Teresa, Carcereny, Enric, Morales-Espinosa, Daniela, Bosch-Barrera, Joaquim, Sperduti, Isabella, Molina-Vila, Miguel Angel, Rosell, Rafael, Crisetti, Elisabetta, Felipe Cardona, Andrés

2015

Overview

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 IC 50 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/106 / 38 / 38/77 / 38/90 / 631/67/1612/1350 / 631/67/1857 / 82/83 / Adenocarcinoma / Aged / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Apoptosis Regulatory Proteins - genetics / Apoptosis Regulatory Proteins - metabolism / Bcl-2-Like Protein 11 / BIM protein / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Cell activation / Cell proliferation / Cohort Studies / Disease-Free Survival / Epidermal growth factor receptors / ErbB Receptors - genetics / Erlotinib Hydrochloride - pharmacology / Erlotinib Hydrochloride - therapeutic use / Female / Gefitinib / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Humanities and Social Sciences / Humans / Inhibitor drugs / Inhibitory Concentration 50 / Kinases / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Male / Membrane Proteins - genetics / Membrane Proteins - metabolism / Middle Aged / Mortality risk / multidisciplinary / Mutants / Mutation - genetics / Non-small cell lung carcinoma / Phosphodiesterase / Protein-tyrosine kinase / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Quinazolines - pharmacology / Quinazolines - therapeutic use / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Signal Transduction - drug effects / Signal Transduction - genetics / Small cell lung carcinoma / Targeted cancer therapy / TOR protein / TOR Serine-Threonine Kinases - genetics / TOR Serine-Threonine Kinases - metabolism / Treatment Outcome / Tumor cell lines