title: Epithelial-Mesenchymal Transition Predicts Polo-Like Kinase 1 Inhibitor-Mediated Apoptosis in Non-Small Cell Lung Cancer.
abstract: OBJECTIVE
  To identify new therapeutic targets for non-small cell lung cancer (NSCLC), we systematically searched two cancer cell line databases for sensitivity data on a broad range of drugs. We identified polo-like kinase 1 (PLK1) as the most promising target for further investigation based on a subset of sensitive NSCLC cell lines and inhibitors that were in advanced clinical development.
  
  
  METHODS
  To identify potential biomarkers of response of NSCLC to PLK1 inhibition and mechanisms of PLK1 inhibitor-induced apoptosis, integrated analysis of gene and protein expression, gene mutations, and drug sensitivity was performed using three PLK1 inhibitors (volasertib, BI2536, and GSK461364) with a large panel of NSCLC cell lines.
  
  
  RESULTS
  The NSCLC cell lines had different sensitivities to PLK1 inhibition, with a minority demonstrating sensitivity to all three inhibitors. PLK1 inhibition led to G2-M arrest, but only treatment-sensitive cell lines underwent substantial apoptosis following PLK1 inhibition. NSCLC lines with high epithelial-mesenchymal transition (EMT) gene signature scores (mesenchymal cell lines) were more sensitive to PLK1 inhibition than epithelial lines (P< 0.02). Likewise, proteomic profiling demonstrated that E-cadherin expression was higher in the resistant cell lines than in the sensitive ones (P< 0.01). Induction of an epithelial phenotype by expression of the miRNA miR-200 increased cellular resistance to PLK1 inhibition. Also, KRAS mutation and alterations in the tight-junction, ErbB, and Rho signaling pathways correlated with drug response of NSCLC.
  
  
  CONCLUSIONS
  In this first reported large-scale integrated analysis of PLK1 inhibitor sensitivity, we demonstrated that EMT leads to PLK1 inhibition sensitivity of NSCLC cells. Our findings have important clinical implications for mesenchymal NSCLC, a significant subtype of the disease that is associated with resistance to currently approved targeted therapies.
authors.affiliation: Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Renata
authors.initials: R
authors.lastname: Ferrarotto
authors.affiliation: Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: Ruchitha
authors.initials: R
authors.lastname: Goonatilake
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Suk Young
authors.initials: SY
authors.lastname: Yoo
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Pan
authors.initials: P
authors.lastname: Tong
authors.affiliation: Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Uma
authors.initials: U
authors.lastname: Giri
authors.affiliation: Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Peng
authors.affiliation: Hamon Cancer Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: John
authors.initials: J
authors.lastname: Minna
authors.affiliation: Hamon Cancer Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, China.
authors.forename: Liguang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lerong
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.affiliation: Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: David H
authors.initials: DH
authors.lastname: Peng
authors.affiliation: Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.affiliation: Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bonnie S
authors.initials: BS
authors.lastname: Glisson
authors.affiliation: Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.|Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Byers
authors.affiliation: Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011621:Pteridines / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011621:Pteridines; D013876:Thiophenes; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C561573:GSK 461364; C117307:KRAS protein, human