Abstract 348: Comparison of the response of the NCI60 NSCLC panel with the response of patient-derived NSCLC lines to approved and investigational agents

Abstract

Abstract An 800 compound screen with the NCI60 cell lines and 5 patient-derived NSCLC lines (PD NSCLC), was conducted at 9 concentrations and included the FDA approved oncology agents and an investigational agents library. The screen was conducted using 384-well monolayer cultures, an exposure time of 72 hrs and compound concentrations from 1 nM to 10 uM. CellTiter-Glo was used to measure viability as an endpoint. The NCI60 NSCLC panel consists of 9 cell lines: A549, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460 and NCI-H522. The response of these lines was compared with the response of 5 PD NSCLC lines and 60 SCLC lines. While both sets of NSCLC lines had similar responses to the majority of compounds, there were some marked differences. Differences in response of the NCI60 NSCLC lines and the PD NSCLC lines were notable upon exposure to tubulin fragmenters, KSP/EG5 inhibitors, GAR transformylase inhibitors, Polo-like kinase-1 inhibitors (PLK1), MEK inhibitors, and IAP inhibitors. The NCI60 NSCLC lines were more sensitive to the tubulin fragmenters than were the PD NSCLC and the SCLC lines. Verubulin had a mean GI50 in NCI60 NSCLC of 0.0037 uM and 0.0042 uM in SCLC versus 0.047uM in the PD NSCLC lines. The NCI60 NSCLC lines were more sensitive to the KSP inhibitor, ARRY-520 (mean GI50 0.0049 uM) than the SCLC lines (0.028 uM) and the PD NSCLC lines (0.26 uM). The NCI60 NSCLC lines (mean GI50 0.019 uM) and the SCLC lines (mean GI50 0.04 uM) were more sensitive to PLK1 inhibitors such as BI-2536 than the PD NSCLC lines (0.13 uM). However, the NCI60 NSCLC lines (mean GI50 0.8 uM) and the SCLC lines (mean GI50 0.134 uM) were less sensitive than the PD NSCLC lines (mean GI50 0.025uM) to GAR transformylase inhibitors such as pelitrexol. The NCI60 NSCLC lines (mean GI50 6.3 uM) and SCLC lines (mean GI50 10 uM) were also less responsive to IAP inhibitors, than were PD NSCLC lines (mean GI50 1.6 uM). A heterogeneous response to the MEK inhibitors such as cobimetinib (GDC-0973) was observed with the SCLC lines (mean GI50 8.9 uM) versus 1.15 uM in the NCI60 NSCLC lines and 0.56 uM in the PD NSCLC lines. PD NSCLC lines exhibit some interesting differences in response from established lung cancer lines upon in vitro exposure to anticancer agents and thus add to our knowledge and understanding of NSCLC and help inform discovery efforts and/or clinical development of therapeutics in this disease. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E. Citation Format: Beverly A. Teicher, David Evans, Thomas Silvers, Michael Selby, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Joel Morris, Gurmeet Kaur, James Doroshow. Comparison of the response of the NCI60 NSCLC panel with the response of patient-derived NSCLC lines to approved and investigational agents [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 348. doi:10.1158/1538-7445.AM2017-348