title: Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients.
abstract: Significant improvements in the outcome of non-small cell lung carcinoma (NSCLC) have been reported in patients treated with the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. To discover biomarkers for the enrichment of patients who might benefit from treatment, a pharmacogenomic approach was used to identify gene signatures that may predict erlotinib activity using in vitro model systems. Erlotinib sensitivity in a panel of 42 NSCLC cell lines was determined by EGFR-mediated proliferative potential, EGFR mutations, and/or EGFR gene amplification, thus supporting an underlying biological mechanism of receptor activation. A strong multigene signature indicative of an epithelial to mesenchymal transition (EMT) was identified as a determinant of insensitivity to erlotinib through both supervised and unsupervised gene expression approaches. This observation was further supported by expression analysis of classic EMT marker proteins, including E-cadherin and vimentin. To investigate the clinical relevance of these findings, we examined expression of the epithelial marker E-cadherin by immunohistochemistry on primary tumor samples from subjects enrolled in a randomized NSCLC clinical trial in which erlotinib in combination with chemotherapy previously failed to show clinical activity. The majority (75%) of the 87 subjects tested showed strong E-cadherin staining and exhibited a significantly longer time to progression (hazard ratio, 0.37; log rank P=0.0028) and a nonsignificant trend toward longer survival with erlotinib plus chemotherapy treatment versus chemotherapy alone. These data support a potential role for EMT as a determinant of EGFR activity in NSCLC tumor cells and E-cadherin expression as a novel biomarker predicting clinical activity of the EGFR inhibitor erlotinib in NSCLC patients.
authors.affiliation: Department of Molecular Diagnostics, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.forename: Thomas
authors.initials: T
authors.lastname: Januario
authors.forename: David A
authors.initials: DA
authors.lastname: Eberhard
authors.forename: Guy
authors.initials: G
authors.lastname: Cavet
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhu
authors.forename: Ling
authors.initials: L
authors.lastname: Fu
authors.forename: Thinh Q
authors.initials: TQ
authors.lastname: Pham
authors.forename: Robert
authors.initials: R
authors.lastname: Soriano
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Lin
authors.forename: Vincent
authors.initials: V
authors.lastname: O'Neill
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Amler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D015820:Cadherins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004848:Epithelium / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005784:Gene Amplification; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D008648:Mesoderm / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014746:Vimentin / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015820:Cadherins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014746:Vimentin; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors