Abstract 4831: Small cell lung carcinoma (SCLC) cell line screen of standard of care (etoposide/carboplatin) plus a third agent

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 >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 r