Abstract 6073: First-in-class Doublecortin-like kinase 1 (DCLK1) inhibitor for targeting cancer stem cell in hepatocellular carcinoma

Abstract

Abstract Cancer stem cells (CSCs) have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. Doublecortin-like kinase 1 (DCLK1) was recently identified as CSC marker is upregulated in several solid tumors, which distinguishes between cancer and normal stem cell. However, the role of DCLK1 in hepatocellular carcinoma (HCC) is unclear. According to the open database like TCGA, overexpression of DCLK1 is reported to be associated with poor prognosis in HCC patients. It was also observed that DCLK1 expression was significantly increased in the advanced stage of HCC. In addition, as a result of measuring the serum DCLK1 levels obtained from patients with liver cirrhosis or HCC treated at Seoul National University Hospital, it was confirmed that the expression of DCLK1 was significantly increased in patients with HCC compared to those with liver cirrhosis. It was also confirmed that DCLK1 was expressed in human HCC cell lines and that the expression levels of DCLK1 mRNA and protein were further increased in CSC rich human HCC cell lines. Moreover, cell death was increased at the cellular level when DCLK1 was blocked via inhibiting expression of CSC markers such as CD133 and EpCAM. After evaluating the effect of DCLK1 inhibition in CSC rich human HCC cells lines, it was found that spheroid formation decreased by suppressing CSCs markers including LGR5 and CD133. In addition, it was confirmed that cell migration decreased when DCLK1 was blocked. Even in the murine HCC model, it was found that the antitumor effect was showed when administered with DCLK1 inhibitor, DCLK1-IN-1, in xenograft model with CSC rich HCC cell lines. Our results support that DCLK1 can be used as a biomarker for the detection of HCC and may be a candidate for developing targeted therapeutics to eradicate HCC. Citation Format: Daseul Yoon, Seung Hee Jung, Ju Young Jang, Ji-Young Ahn, Seung Jin Jo, Donghyun Ko, Dong-kyu Kim, Su Jong Yu. First-in-class Doublecortin-like kinase 1 (DCLK1) inhibitor for targeting cancer stem cell in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6073.