title: Loss of cytoplasmic CDK1 predicts poor survival in human lung cancer and confers chemotherapeutic resistance.
abstract: The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery.
authors: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Chunyu
authors: C
authors: Zhang
authors: Abdel G
authors: AG
authors: Elkahloun
authors: Matthew
authors: M
authors: Robertson
authors: Joell J
authors: JJ
authors: Gills
authors: Junji
authors: J
authors: Tsurutani
authors: Joanna H
authors: JH
authors: Shih
authors: Junya
authors: J
authors: Fukuoka
authors: M Christine
authors: MC
authors: Hollander
authors: Curtis C
authors: CC
authors: Harris
authors: William D
authors: WD
authors: Travis
authors: Jin
authors: J
authors: Jen
authors: Phillip A
authors: PA
authors: Dennis
mesh_terms: D016203:CDC2 Protein Kinase / Q000032:analysis* / Q000235:genetics; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D011237:Predictive Value of Tests; D011379:Prognosis; D015996:Survival Rate
chemical_list: D016203:CDC2 Protein Kinase