title: Epithelial membrane protein-1 is a biomarker of gefitinib resistance.
abstract: We describe a molecular resistance biomarker to gefitinib, epithelial membrane protein-1 (EMP-1). Gefitinib is a small-molecule inhibitor that competes for the ATP-binding site on EGF receptor (EGFR) and has been approved for patients with advanced lung cancers. Treatment with gefitinib has resulted in clinical benefit in patients, and, recently, heterozygous somatic mutations within the EGFR catalytic domain have been identified as a clinical correlate to objective response to gefitinib. However, clinical resistance to gefitinib limits the utility of this therapeutic to a fraction of patients, and objective clinical responses are rare. We aimed to assess the molecular phenotype and mechanism of in vivo gefitinib resistance in xenograft models and in patient samples. We generated in vivo gefitinib-resistance models in an adenocarcinoma xenograft model by serially passaging tumors in nude mice in presence of gefitinib until resistance was acquired. EMP-1 was identified as a surface biomarker whose expression correlated with acquisition of gefitinib resistance. EMP-1 expression was further correlated with lack of complete or partial response to gefitinib in lung cancer patient samples as well as clinical progression to secondary gefitinib resistance. EMP-1 expression and acquisition of gefitinib clinical resistance was independent of gefitinib-sensitizing EGFR somatic mutations. This report suggests the role of the adhesion molecule, EMP-1, as a biomarker of gefitinib clinical resistance, and further suggests a probable cross-talk between this molecule and the EGFR signaling pathway.
authors.affiliation: Louis Warschaw Prostate Cancer Center, Los Angeles, CA 90048, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Jain
authors.forename: Charles A
authors.initials: CA
authors.lastname: Tindell
authors.forename: Isett
authors.initials: I
authors.lastname: Laux
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Hunter
authors.forename: John
authors.initials: J
authors.lastname: Curran
authors.forename: Anna
authors.initials: A
authors.lastname: Galkin
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Afar
authors.forename: Nina
authors.initials: N
authors.lastname: Aronson
authors.forename: Steven
authors.initials: S
authors.lastname: Shak
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Natale
authors.forename: David B
authors.initials: DB
authors.lastname: Agus
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D000077156:Gefitinib; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D011799:Quinazolines; D011956:Receptors, Cell Surface; C097051:epithelial membrane protein-1; D000077156:Gefitinib