title: Pharmacogenomic approach to identify drug sensitivity in small-cell lung cancer.
abstract: There are currently no molecular targeted approaches to treat small-cell lung cancer (SCLC) similar to those used successfully against non-small-cell lung cancer. This failure is attributable to our inability to identify clinically-relevant subtypes of this disease. Thus, a more systematic approach to drug discovery for SCLC is needed. In this regard, two comprehensive studies recently published in Nature, the Cancer Cell Line Encyclopedia and the Cancer Genome Project, provide a wealth of data regarding the drug sensitivity and genomic profiles of many different types of cancer cells. In the present study we have mined these two studies for new therapeutic agents for SCLC and identified heat shock proteins, cyclin-dependent kinases and polo-like kinases (PLK) as attractive molecular targets with little current clinical trial activity in SCLC. Remarkably, our analyses demonstrated that most SCLC cell lines clustered into a single, predominant subgroup by either gene expression or CNV analyses, leading us to take a pharmacogenomic approach to identify subgroups of drug-sensitive SCLC cells. Using PLK inhibitors as an example, we identified and validated a gene signature for drug sensitivity in SCLC cell lines. This gene signature could distinguish subpopulations among human SCLC tumors, suggesting its potential clinical utility. Finally, circos plots were constructed to yield a comprehensive view of how transcriptional, copy number and mutational elements affect PLK sensitivity in SCLC cell lines. Taken together, this study outlines an approach to predict drug sensitivity in SCLC to novel targeted therapeutics.
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Gary
authors.initials: G
authors.lastname: Wildey
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: Lent
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Stetson
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Pink
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Jill S
authors.initials: JS
authors.lastname: Barnholtz-Sloan
authors.affiliation: Case Comprehensive Cancer Center and the Division of Hematology and Oncology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010597:Pharmacogenetics
chemical_list: D000970:Antineoplastic Agents