Small Cell Lung Cancer Screen of Oncology Drugs, Investigational Agents, and Gene and microRNA Expression

Eric Polley, Mark Kunkel, David Evans, Thomas Silvers, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Michael Selby, John Connelly, Erik Harris, Nicole Fer, Dmitriy Sonkin, Gurmeet Kaur, Anne Monks, Shakun Malik, Joel Morris, Beverly A. Teicher

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Background: Small cell lung carcinoma (SCLC) is an aggressive, recalcitrant cancer, often metastatic at diagnosis and unresponsive to chemotherapy upon recurrence, thus it is challenging to treat. Methods: Sixty-three human SCLC lines and three NSCLC lines were screened for response to 103 US Food and Drug Administration-approved oncology agents and 423 investigational agents. The investigational agents library was a diverse set of small molecules that included multiple compounds targeting the same molecular entity. The compounds were screened in triplicate at nine concentrations with a 96-hour exposure time using an ATP Lite endpoint. Gene expression was assessed by exon array, and microRNA expression was derived by direct digital detection. Activity across the SCLC lines was associated with molecular characteristics using pair-wise Pearson correlations. Results: Results are presented for inhibitors of targets: BCL2, PARP1, mTOR, IGF1R, KSP/Eg5, PLK-1, AURK, and FGFR1. A relational map identified compounds with similar patterns of response. Unsupervised microRNA clustering resulted in three distinct SCLC subgroups. Associating drug response with micro-RNA expression indicated that lines most sensitive to etoposide and topotecan expressed high miR-200c-3p and low miR-140-5p and miR-9-5p. The BCL-2/BCL-XL inhibitors produced similar response patterns. Sensitivity to ABT-737 correlated with higher ASCL1 and BCL2. Several classes of compounds targeting nuclear proteins regulating mitosis produced a response pattern distinct from the etoposide response pattern. Conclusions: Agents targeting nuclear kinases appear to be effective in SCLC lines. Confirmation of SCLC line findings in xenografts is needed. The drug and compound response, gene expression, and microRNA expression data are publicly available at http://sclccelllines.cancer.gov.

Original languageEnglish (US)
Article numberdjw122
JournalJournal of the National Cancer Institute
Volume108
Issue number10
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Polley, E., Kunkel, M., Evans, D., Silvers, T., Delosh, R., Laudeman, J., Ogle, C., Reinhart, R., Selby, M., Connelly, J., Harris, E., Fer, N., Sonkin, D., Kaur, G., Monks, A., Malik, S., Morris, J., & Teicher, B. A. (2016). Small Cell Lung Cancer Screen of Oncology Drugs, Investigational Agents, and Gene and microRNA Expression. Journal of the National Cancer Institute, 108(10), [djw122]. https://doi.org/10.1093/jnci/djw122