Abstract 972: Pharmacological targeting CDC7 sensitizes oxaliplatin treatment in colorectal cancer

Abstract The cell division cycle 7 (CDC7) is a serine/threonine kinase that plays a critical role in the initiation of DNA replication by phosphorylating MCM 2-7 complex, which is frequently overexpressed in various human cancers. This study aimed to investigate the roles of CDC7 in colorectal cancer (CRC) and its potential pharmacological value. We found CDC7 expression was associated with tumor recurrence and poor outcome in CRC patients. We depleted CDC7 expression with siRNA and found CDC7 depletion dramatically inhibits colony formation in CRC cells treated with oxaliplatin. Importantly, pharmacological inhibition of CDC7 with inhibitor (XL413 or PHA767491) could overcome oxaliplatin resistance of CRC cells in cells proliferation, clone formation and tumorsphere formation. To further validated these findings in vivo, we examined the efficacy of CDC7 inhibitor and oxaliplatin in a DLD1-derived xenograft mouse model and two PDX models. The combination of oxaliplatin and XL413 significantly inhibit xenograft tumor growth, which showed remarkably decreased Ki-67 and increased cleaved-caspase 3 by IHC analysis. Collectively, our findings unveil the critical role of CDC7 in colon cancer cells and targeting CDC7 is a potential effective therapeutic for CRC patients. Citation Format: Yufeng Chen, Zhaoliang Yu, Peng Deng, Xiaojian Wu. Pharmacological targeting CDC7 sensitizes oxaliplatin treatment in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 972.