The therapeutic effect of KSP inhibitors in preclinical models of cholangiocarcinoma

Yuanyuan Shi; Xiaowen Cui; Tianyi Jiang; Yufei Pan; Yunkai Lin; Xiaofan Feng; Zhiwen Ding; Chun Yang; Yexiong Tan; Hongyang Wang; Liwei Dong

doi:10.1038/s41419-022-05247-0

The therapeutic effect of KSP inhibitors in preclinical models of cholangiocarcinoma

Cell Death Dis. 2022 Sep 19;13(9):799. doi: 10.1038/s41419-022-05247-0.

Authors

Yuanyuan Shi^#^{1

2}, Xiaowen Cui^#^{1

3}, Tianyi Jiang^#^{1

3}, Yufei Pan^{1

3}, Yunkai Lin^{1

3}, Xiaofan Feng¹, Zhiwen Ding⁴, Chun Yang⁵, Yexiong Tan¹, Hongyang Wang^{6

7

8}, Liwei Dong^{9

10}

Affiliations

¹ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, the Naval Medical University, Shanghai, 200438, China.
² the First Affiliated Hospital of the Naval Medical University, Shanghai, 200433, China.
³ National Center for Liver Cancer, the Naval Medical University, Shanghai, 201805, China.
⁴ Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
⁵ Children's Hospital of Soochow University, Suzhou, 215025, China.
⁶ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, the Naval Medical University, Shanghai, 200438, China. hywangk@vip.sina.com.
⁷ National Center for Liver Cancer, the Naval Medical University, Shanghai, 201805, China. hywangk@vip.sina.com.
⁸ Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. hywangk@vip.sina.com.
⁹ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, the Naval Medical University, Shanghai, 200438, China. dlw@smmu.edu.cn.
¹⁰ National Center for Liver Cancer, the Naval Medical University, Shanghai, 201805, China. dlw@smmu.edu.cn.

^# Contributed equally.

Abstract

Cholangiocarcinoma (CCA) is an epithelial malignancy with a dismal prognosis owing to limited treatment options. Here, we identified several compound candidates against CCA using a high-throughput drug screen with approved or emerging oncology drugs, among which kinesin spindle protein (KSP) inhibitors showed potent cytotoxic effects on CCA cells. Treatment with KSP inhibitors SB743921 and ARRY520 caused significant tumor suppression in CCA xenograft models in vivo. Mechanistically, KSP inhibitors led to the formation of abnormal monopolar spindles, which further resulted in the mitotic arrest and cell death of CCA cells both in vivo and in vitro. KEGG pathway analysis of transcriptional data confirmed this finding. Moreover, our clinical data as well as the TCGA database showed KIF11 expression was abundant in most CCA tumor specimens and associated with poor outcomes of CCA patients. Our results demonstrate that the therapeutic regimen of KSP inhibitors could be a promising treatment strategy in CCA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Bile Duct Neoplasms* / drug therapy
Bile Duct Neoplasms* / genetics
Bile Ducts, Intrahepatic
Cholangiocarcinoma* / drug therapy
Cholangiocarcinoma* / genetics
Humans
Kinesins / genetics

Substances

Antineoplastic Agents
Kinesins