title: Two novel determinants of etoposide resistance in small cell lung cancer.
abstract: Patient survival in small cell lung cancer (SCLC) is limited by acquired chemoresistance. Here we report the use of a biologically relevant model to identify novel candidate genes mediating in vivo acquired resistance to etoposide. Candidate genes derived from a cDNA microarray analysis were cloned and transiently overexpressed to evaluate their potential functional roles. We identified two promising genes in the DNA repair enzyme DNA polymerase β and in the neuroendocrine transcription factor NKX2.2. Specific inhibition of DNA polymerase β reduced the numbers of cells surviving treatment with etoposide and increased the amount of DNA damage in cells. Conversely, stable overexpression of NKX2.2 increased cell survival in response to etoposide in SCLC cell lines. Consistent with these findings, we found that an absence of nuclear staining for NKX2.2 in SCLC primary tumors was an independent predictor of improved outcomes in chemotherapy-treated patients. Taken together, our findings justify future prospective studies to confirm the roles of these molecules in mediating chemotherapy resistance in SCLC.
authors.affiliation: Cancer Research UK Cambridge Research Institute; Department of Oncology, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom.
authors.forename: Malcolm H
authors.initials: MH
authors.lastname: Lawson
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Cummings
authors.forename: Doris M
authors.initials: DM
authors.lastname: Rassl
authors.forename: Roslin
authors.initials: R
authors.lastname: Russell
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rintoul
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019951:DNA Polymerase beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715631:NKX2-2 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; D005047:Etoposide; D019951:DNA Polymerase beta