Abstract 2956: Inhibition of CHK1 sensitizes Ewing sarcoma cells to CDK1-dependent cell death in S-phase

Abstract

Abstract Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. The treatment of Ewing sarcoma has changed very little in the past two decades and novel treatment approaches are needed. We recently identified that Ewing sarcoma cells are uniquely vulnerable to inhibitors of ribonucleotide reductase (RNR), the rate limiting enzyme in the synthesis of deoxyribonucleotides. We subsequently found that the inhibition of checkpoint kinase 1 (CHK1) increases the sensitivity of Ewing sarcoma cells to inhibitors of RNR, such as gemcitabine. The ATR-CHK1 pathway, from a mechanistic standpoint, regulates multiple stages of the cell cycle, including S-phase, the G2/M transition, and M phase. In the current work, we used cell synchronization to identify that the inhibition of CHK1 in S-phase cells results in premature entry into mitosis and cell death. Similarly, the inhibition of ATR serine/threonine kinase (ATR), the upstream activator of CHK1, also causes Ewing sarcoma cells to inappropriately enter mitosis. Moreover, we have found in Ewing sarcoma cells that this aberrant entry into mitosis is mediated, in part, by cyclin dependent kinase 1 (CDK1). In addition, activation of CDK1 by inhibiting the WEE1 kinase with AZD1775 also results in entry into mitosis and cell death in Ewing sarcoma cells. Currently, ongoing work is focused on the in vivo testing of gemcitabine in combination with CHK1 and WEE1 inhibitors as a novel therapeutic approach for the treatment of Ewing sarcoma. Citation Format: David Gordon, Kelli Goss, Stacia Koppenhafer. Inhibition of CHK1 sensitizes Ewing sarcoma cells to CDK1-dependent cell death in S-phase [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 2956.