title: BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer.
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.
authors.affiliation: Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain.
authors.forename: Niki
authors.initials: N
authors.lastname: Karachaliou
authors.affiliation: Pangaea Biotech, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Codony-Servat
authors.affiliation: Pangaea Biotech, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Teixidó
authors.affiliation: Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pilotto
authors.affiliation: Pivotal, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Drozdowskyj
authors.affiliation: Pangaea Biotech, Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Codony-Servat
authors.affiliation: Pangaea Biotech, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Giménez-Capitán
authors.affiliation: Pangaea Biotech, Barcelona, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Molina-Vila
authors.affiliation: Pangaea Biotech, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bertrán-Alamillo
authors.affiliation: Centre François Baclesse, Caen, France.
authors.forename: Radj
authors.initials: R
authors.lastname: Gervais
authors.affiliation: Hospital General de Alicante, Alicante, Spain.
authors.forename: Bartomeu
authors.initials: B
authors.lastname: Massuti
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Morán
authors.affiliation: Hospital de Sant Pau, Barcelona, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Majem
authors.affiliation: Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Felip
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Carcereny
authors.affiliation: Complexo Hospitalario Universitario La Coruña, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: García-Campelo
authors.affiliation: Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Viteri
authors.affiliation: Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: González-Cao
authors.affiliation: Instituto Oncológico Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain.
authors.forename: Daniela
authors.initials: D
authors.lastname: Morales-Espinosa
authors.affiliation: Ospedale Santa Maria delle Croci, Ravenna, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Verlicchi
authors.affiliation: Department of Medical and Surgical Sciences, Institute of Respiratory Diseases, University of Foggia, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Crisetti
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Imane
authors.initials: I
authors.lastname: Chaib
authors.affiliation: Medical Oncology Unit, Human Pathology Department, University of Messina, Italy.
authors.forename: Mariacarmela
authors.initials: M
authors.lastname: Santarpia
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Luis Ramírez
authors.affiliation: Catalan Institute of Oncology, Hospital Josep Trueta, Girona, Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bosch-Barrera
authors.affiliation: Clinical and Traslational Oncology Group, Institute of Oncology, Clínica del Country, Bogotá, Colombia.
authors.forename: Andrés
authors.initials: A
authors.lastname: Felipe Cardona
authors.affiliation: Direttore, Divisione di Oncologica Toracica, Istituto Europeo di Oncologia-IEO, Milano, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Marinis
authors.affiliation: Chief, Medical Oncology Service, Hospital de Cruces, Barakaldo, Vizcaya, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: López-Vivanco
authors.affiliation: Medical Oncology Service, Hospital de la Princesa, Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Miguel Sánchez
authors.affiliation: Hôpital du Cluzeau, Limoges, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Vergnenegre
authors.affiliation: Unidad de Investigación en Salud Pública CIDICS-UANL.
authors.forename: José Javier
authors.initials: JJ
authors.lastname: Sánchez Hernández
authors.affiliation: Biostatistics, Regina Elena National Cancer Institute, Rome.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Department of Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.affiliation: 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.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D012333:RNA, Messenger; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D000077156:Gefitinib