Abstract 5406: Osteosarcoma cell lines response to approved and investigational anticancer agents and statins along with gene and microRNA expression

Abstract

Abstract Background: Sarcomas are rare heterogeneous cancers with significant unmet medical need. Approved and Investigational compounds were tested against 64 human sarcoma cell lines. Gene expression was determined using Affymetrix Exon ST1 arrays. Eleven of 64 human sarcoma lines were osteosarcoma. Methods: 64 adult and pediatric sarcoma lines were screened against the approved and investigational agents. Compounds were screened in 9-pt concentration response (0.001-10 μM). The cells were cultured in 384-well plates overnight, and then compounds were added (DMSO, 0.25%). Viability was determined after 96h using Alamar Blue. In separate experiments, the response of the osteosarcoma lines to 9 statins was assessed at 9 concentrations with a 96h exposure time and CellTiter-Glo® as endpoint. Concentration response curves and IC50′s were determined from an average of 3 experiments. Gene expression was determined by the Exon ST1 array. MicroRNA expression was determined using the NanoString human miRNA probe set on the nCounter® Prep Station followed by immobilization in the cartridge for data collection. Results: The genes highly differentially expressed by the osteosarcoma lines, RUNX2, CDC42EP3, CGNT1, EHD4 and EST1, were compared with simvastatin (NSC633782) sensitivity. The response of the osteosarcoma lines to 9 statins showed that pitavastatin (NSC779706) was most effective with IC50 ranging from 0.2 - 5 μM. The SAOS-2 line was most responsive to the statins. Overall, the synthetic statins (fluvastatin, pitavastatin and atorvastatin) were more effective against the osteosarcoma cell lines than the fermentation-derived statins. Among the fermentation-derived statins, simvastatin had the most similarity in potency and pattern to the synthetic statins. All ten osteosarcoma cell lines tested were resistant to pravastatin, rosvustatin, and bestatin (IC50>10μM). ERBB4 was highly expressed in 3 of 11 osteosarcoma lines. These 3 lines were the most sensitive to 13 EGFR inhibitors tested. SAOS-2 cells express high FGFR2 and KIT, CHA59 cells express high FGFR3 and SK-ES-1 cells highly express KIT. Eighteen approved and investigational broad spectrum kinase inhibitors and selective FGFR, KIT and MET inhibitors were tested. The most sensitive osteosarcoma lines were SK-ES-1, CHA59, HOS, and Hu09 while SA-OS-2 was less sensitive. MYC, MYCL1, and MYCN gene expression indicated that SAOS-2, OHS, CHA59 and SK-ES-1 express high MYC. OHS, SK-ES-1, CHA59, HOS and Hu09 cells were sensitive to the two bromodomain inhibitors tested, JQ1 and GSK-1210151A, while SAOS-2 was less sensitive. The SJSA-1 line expresses high GLI1, PTCH1 and PTCH2. Five SMO inhibitors were tested and only the Hu09 cells responded. Conclusions: Testing investigational agents in a panel of sarcoma cell lines along with molecular characterization may help identify new drugs worthy of clinical trial in sarcoma. Citation Format: Gurmeet Kaur, Eric Polley, Joel Morris, Thomas Silvers, Michael Selby, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Anne Monks, Annamaria Rapisarda, David Evans, Beverly A. Teicher. Osteosarcoma cell lines response to approved and investigational anticancer agents and statins along with gene and microRNA expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5406. doi:10.1158/1538-7445.AM2015-5406