Abstract Small cell lung cancer (SCLC) is an aggressive cancer with a 5-year survival rate of <5%. While initially responsive to treatments with platinum agents, topoisomerase inhibitors or methotrexate, the tumors frequently recur after chemotherapy. To identify whether approved small molecule drugs or investigational agents may have unexpected effects in SCLC lines, we undertook a systematic large-scale screen with >500 compounds against > 60 well characterized SCLC cell lines in culture. Cells were exposed to 101 Approved Oncology Drugs (AOD) and 433 Investigational Agents. By evaluating compounds at 9 concentrations (10uM to 1.5nM), using cell viability 96h post drug exposure as the endpoint (Cell Titer Glo), we were able to obtain concentration response curves and IC50 values for the compounds and rank activity of these agents. In parallel studies, using Affymetrix exon ST1 arrays and miRNA profiling, we examined these same cell lines for differences in gene expression patterns that may correlate with sensitivity or resistance to select agents in the screen. The Myc oncogene (cMyc, LMyc, or nMyc) is over-expressed in about 40% of SCLC lines. Surprisingly, early analyses of the SCLC screen data have been unable to correlate high Myc expression with response to drugs or investigational agents (there is a trend with bromodomain inhibitors). The large majority of SCLC lines were sensitive to compounds against select target classes (e.g. HSP90 inhibitors and HDAC inhibitors). Examining HSP70 and HSP90 levels by Western blot suggested a slight reduction in HSP90 levels in cells resistant to the HSP90 inhibitor Ganetespib with no change in HSP70 levels. Some inhibitors against these targets showed broader cell activity than others. We are currently determining whether such differential drug sensitivity is correlated with specific changes in gene expression patterns in these cells. Further data analyses from the screen combined with genomic profiling of the cells will be presented. Funded by NCI Contract No. HHSN261200800001E. Citation Format: David M. Evans, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Michael Selby, Thomas Silvers, John Connelly, Anne Monks, Eric Polley, Gurmeet Kaur, Joel Morris, Beverly Teicher. Screening more than 60 human SCLC lines with approved and investigational agents indicates complex patterns of response: Identification of HSP90 and HDACs as potential targets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5450. doi:10.1158/1538-7445.AM2014-5450