title: Biomarkers of erlotinib response in non-small cell lung cancer tumors that do not harbor the more common epidermal growth factor receptor mutations.
abstract: Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancers, which are the leading cause of cancer-related deaths in the world. Tyrosine kinase inhibitors such as erlotinib represent one therapeutic options presently recommended for tumors produced by activating mutations in the gene coding of epidermal growth factor receptor (EGFR). The aim of this study is the identification of possible biomarkers for tumor sensitivity to erlotinib in the absence of the main EGFR mutations. The erlotinib sensitivity of cells isolated from 41 untreated NSCLC patients was determined and compared with the presence of the more frequent EGFR mutations. Several patients had tumor cells highly sensitive to erlitinib in the absence of the EGFR mutations analyzed. The gene expression profile of 3 erlotinib-sensitive tumors was compared with that of 4 resistant tumors by DNA microarray hybridization. Sixteen genes were expressed at significantly higher levels in the resistant tumors than in the sensitive tumors. The possible correlation between erlotinib sensitivity and the expression of these genes was further analyzed using the data for the NSCLC, breast cancer and colon cancer cell lines of the NCI60 collection. The expression of these genes was correlated with the overall survival of 5 patients treated with erlotinib, according to The Cancer Genome Atlas (TCGA) database. Overlapping groups of 7, 5 and 3 genes, including UGT1A6, TRIB3, MET, MMP7, COL17A1, LCN2 and PTPRZ1, whose expression correlated with erlotinib activity was identified. In particular, low MET expression levels showed the strongest correlation.
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM; Biomarkers and Experimental Therapeutics in Cancer, IdiPaz Madrid, Spain.
authors.forename: Blanca D
authors.initials: BD
authors.lastname: López-Ayllón
authors.affiliation: Department of Medical Oncology, La Paz University Hospital, IdiPaz Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: de Castro-Carpeño
authors.affiliation: Cancer Epigenetics Laboratory, INGEMM, Biomarkers and Experimental Therapeutics in Cancer, IdiPaz, La Paz University Hospital Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez
authors.affiliation: Cancer Epigenetics Laboratory, INGEMM, Biomarkers and Experimental Therapeutics in Cancer, IdiPaz, La Paz University Hospital Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Pernía
authors.affiliation: Cancer Epigenetics Laboratory, INGEMM, Biomarkers and Experimental Therapeutics in Cancer, IdiPaz, La Paz University Hospital Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ibañez de Cáceres
authors.affiliation: Department of Medical Oncology, Madrid Norte Sanchinarro University Hospital Madrid, Spain.
authors.forename: Cristobal
authors.initials: C
authors.lastname: Belda-Iniesta
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM; Biomarkers and Experimental Therapeutics in Cancer, IdiPaz Madrid, Spain ; CIBER de Enfermedades Raras Valencia, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Perona
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM; Biomarkers and Experimental Therapeutics in Cancer, IdiPaz Madrid, Spain ; CIBER de Enfermedades Raras Valencia, Spain.
authors.forename: Leandro
authors.initials: L
authors.lastname: Sastre
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Biomarkers; EGFR; MET; erlotinib sensitivity; non-small cell lung cancer