Abstract 4746: Identifying states of collateral sensitivity during the evolution of therapy resistance in Ewing’s sarcoma

Abstract

During the evolution of therapeutic resistance many cancers exhibit a phenomenon termed collateral sensitivity, where resistance to one drug aligns with sensitivity to another drug. It has further been shown, in leukemia and non-small cell lung cancer, that this state of collateral sensitivity can vary over time. We hypothesized that this process will also occur in Ewing’s sarcoma (EWS), and that these phenotypic states can be identified with molecular signatures based on gene expression. The standard chemotherapy for EWS is repeated cycles of two alternating drug cassettes, one is a combination of vincristine, doxorubicin, and cyclophosphamide (VDC), and a second is a combination of ifosfamide and etoposide (IE). This treatment is highly effective, though advanced stage disease often relapses, and then drug resistance invariably develops, a process following the laws of Darwinian evolution. Finding predictable patterns, or signatures, of collateral sensitivity would provide a useful decision support tool in the clinic to help guide chemotherapy choices. Recent studies in other cancers, bacteria, and in silico simulations have explored and identified optimal timing of switching among the drugs of collateral sensitivity to achieving maximal efficacy. To analyze temporal changes in collateral sensitivity in EWS, we exposed two EWS cell lines, A673 and TTC-466, to half maximal inhibitory concentrations of VDC/IE combinations in vitro. As the cultures recovered from drug exposures, we determined their sensitivities against a panel of drugs including the ones used for the treatment and a new generation of drugs that show efficacy against EWS. The new drugs consist of SP2509, pazopanib, olaparib, dactinomycin, temozolomide, vorinostat, and SN-38. We also collected RNA samples to analyze the transcriptomic alterations which correlate with changes in their collateral sensitivity. Significant findings for the A673 cell line include increased resistance to dactinomycin, doxorubicin, etoposide and vincristine for all treatment replicates, and maximal sensitivity to temozolomide halfway through the treatment schedule for all treatment replicates. Notably, every tumor is different and may develop collateral sensitivity at unique time points. Even in this experiment we observe variation between evolutionary replicates that were originally genetically identical. Future work should include investigating a quick and cost-effective method for testing temporal collateral sensitivity of individual tumors so our findings can be implemented clinically. Citation Format: Erin McClure, Masahiro Hitomi, Jessica Scarborough, Jacob Scott. Identifying states of collateral sensitivity during the evolution of therapy resistance in Ewing’s sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4746.