Abstract 4831: Small cell lung carcinoma (SCLC) cell line screen of standard of care (etoposide/carboplatin) plus a third agent
Authors: Beverly A. Teicher, Michael Selby, Thomas Silvers, Julie Laudeman, Russell Reinhart, Rene Delosh, Chad Ogle, Ralph Parchment, Julia Krushkal, Dmitriy Sonkin, Joel Morris, Mark Kunkel, David Evans
Journal: Cancer Research (2017)

Abstract The standard-of-care for limited stage and extensive stage SCLC has remained etoposide and a platinum complex for more than 30 years because 60-80% of patients respond; however, SCLC inevitably recurs. Recurrent SCLC has proven to be resistant to many therapeutics administered as second- or third-line treatments; therefore, combining therapies in the first instance may be a critically useful strategy. A high throughput screen was performed where 62 SCLC lines were exposed to etoposide (0.3uM)/carboplatin (3.7 uM) (E/C) with or without simultaneous exposure to a third agent (n = 220). Viability of the cells was measured using CellTiter-Glo after 96 hr exposure to 9 concentrations of each individual compound or combination with E/C. The test concentrations encompassed the clinical Cmax for each third agent, and the concentrations of E/C selected for the screen were systematically determined to produce SCLC kill that would allow observation of additivity/synergy upon addition of a third agent. IC50s were determined from the concentration response data and showed that the predominant effect of adding a third agent to E/C was additive. Less than additive effects occurred more frequently in SCLC lines that were sensitive to etoposide/carboplatin. Antagonism with E/C occurred in combination with taxanes and tubulin fragmenters such as vinorelbine. Effective single agents such as the nuclear kinase inhibitors (aurora kinase inhibitors, KSP/EG5 inhibitors and polo-like kinase inhibitors) were antagonistic in combination with E/C but were effective single agents. Greater than additive SCLC killing occurred with E/C in combination with several classes of agents. The combination of the Chk1 inhibitor rabusertib with E/C resulted in an IC50 that was &amp;gt;1 log lower than that of rabusertib alone in several SCLC lines. The GSK-3β inhibitor LY-2090314 produced greater than additive SCLC killing in combination with E/C. LY-2090314 had little effect on the SCLC lines alone but the simultaneous combination with E/C resulted in multi-log killing in selected SCLC lines. The BET bromodomain inhibitor MK-8628 was highly effective when combined with E/C as was the PARP1 inhibitor talazoparib in a small subset of the SCLC lines. While many agents have been tested in combination with E/C in SCLC and failed to improve patients’ survival, the findings of this study identified third agents that may represent new leads for the treatment of this recalcitrant disease. Distinct patterns of response in select subsets of the 62 SCLC lines tested may allow identification of biomarkers predictive of the responders to certain 3-drug regimens. This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. Note: This abstract was not presented at the meeting. Citation Format: Beverly A. Teicher, Michael Selby, Thomas Silvers, Julie Laudeman, Russell Reinhart, Rene Delosh, Chad Ogle, Ralph Parchment, Julia Krushkal, Dmitriy Sonkin, Joel Morris, Mark Kunkel, David Evans. Small cell lung carcinoma (SCLC) cell line screen of standard of care (etoposide/carboplatin) plus a third agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4831. doi:10.1158/1538-7445.AM2017-4831