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CT-707 overcomes hypoxia-mediated sorafenib resistance in Hepatocellular carcinoma by inhibiting YAP signaling

  1. Author:
    Chen,Zibo
    Yuan, Tao
    Yan, Fangjie
    Ye, Song
    Xie, Qin
    Zhang, Bo
    Lin, Nengmin
    He, Qiaojun
    Yang, Bo
    Zhu, Hong [ORCID]

  2. Author Address

    Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China., Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, USA., Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China., School of Medicine, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China., Cancer Center of Zhejiang University, Hangzhou, China., Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People 39;s Hospital, Zhejiang University School of Medicine, Hangzhou, China., Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. yang924@zju.edu.cn., Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. hongzhu@zju.edu.cn., Cancer Center of Zhejiang University, Hangzhou, China. hongzhu@zju.edu.cn.,
    1. Year: 2022
    2. Date: Apr 19
    3. Epub Date: 2022 04 19
  2. Journal: BMC Cancer
    1. 22
    2. 1
    3. Pages: 425
  4. Type of Article: Article
  5. Article Number: 425
  1. Abstract:

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib is the first-line treatment for advanced HCC, but the anti-cancer effects remain to be improved as indicated by its low response rates and failure to prolong the progression-free survival (PFS). Thus, it is urgent to explore approaches to improve the clinical outcome. The effect of Sorafenib in HCC was analyzed by SRB (sulforhodamine B) assay in normoxia and hypoxia, respectively. The different dose combination effect of CT707 and sorafenib was analyzed by SRB assay in hypoxia. Flow cytometry assay was used to detect the cell apoptosis rate with CT707 and sorafenib treatment in hypoxia. Western blotting was used to detect the expression levels of apoptosis -related proteins and the mechanism of CT707 overcome the resistance of sorafenib in hypoxia. Our study showed that the characteristic intratumor hypoxia of advanced HCC is one of the major factors which mediated the drug resistance towards sorafenib in HCC. And CT-707, a novel multi-kinase inhibitor, could sensitize the hypoxic HCC cells towards sorafenib. Further studies showed that CT-707 abolished the nuclear translocation of Yes Associate-Protein (YAP), which has been demonstrated as one of mechanism of hypoxia-mediated sorafenib-resistance in HCC. Overall, this study not only favors the development of this novel multi-kinase inhibitor CT-707 as a therapeutic agent against HCC, but also provides a potential strategy to overcome the hypoxia-mediated resistance to sorafenib in HCC patients. © 2022. The Author(s).

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External Sources

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  2. DOI: 10.1186/s12885-022-09520-5
  3. PMID: 35440025
  4. PII : 10.1186/s12885-022-09520-5

Library Notes

  1. Fiscal Year: FY2021-2022
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