2. Academic Validation
  3. Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate

Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate

  • Sci Transl Med. 2021 Feb 3;13(579):eabb6282. doi: 10.1126/scitranslmed.abb6282.
Fan-En Kong 1 2,  Guang-Meng Li 3,  Yun-Qiang Tang 1,  Shao-Yan Xi 4,  Jane Ho Chun Loong 5,  Mei-Mei Li 1 2,  Hao-Long Li 1 2,  Wei Cheng 1 2,  Wen-Jie Zhu 1 2,  Jia-Qiang Mo 6,  Yuan-Feng Gong 1,  Hui Tang 1,  Yue Zhao 7,  Yan Zhang 8,  Stephanie Ma 5,  Xin-Yuan Guan 4 9,  Ning-Fang Ma 1 2,  Mao-Bin Xie 10,  Ming Liu 11 2
Affiliations

Affiliations

  • 1 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, China.
  • 2 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China.
  • 3 The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Department of Biomedical Engineering, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
  • 4 State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 5 School of Biomedical Sciences, State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong 852, Hong Kong.
  • 6 Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
  • 7 General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne 50923, Germany.
  • 8 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
  • 9 Department of Clinical Oncology, State Key Laboratory of Liver Research, University of Hong Kong 852, Hong Kong.
  • 10 The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Department of Biomedical Engineering, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China. [email protected] [email protected].
  • 11 Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, China. [email protected] [email protected].
PMID: 33536280 DOI: 10.1126/scitranslmed.abb6282
Abstract

Tumor lineage plasticity is emerging as a critical mechanism of therapeutic resistance and tumor relapse. Highly plastic tumor cells can undergo phenotypic switching to a drug-tolerant state to avoid drug toxicity. Here, we investigate the transmembrane tight junction protein Claudin6 (CLDN6) as a therapeutic target related to lineage plasticity for hepatocellular carcinoma (HCC). CLDN6 was highly expressed in embryonic stem cells but markedly decreased in normal tissues. Reactivation of CLDN6 was frequently observed in HCC tumor tissues as well as in premalignant lesions. Functional assays indicated that CLDN6 is not only a tumor-associated antigen but also conferred strong oncogenic effects in HCC. Overexpression of CLDN6 induced phenotypic shift of HCC cells from hepatic lineage to biliary lineage, which was more refractory to sorafenib treatment. The enhanced tumor lineage plasticity and cellular identity change were potentially induced by the CLDN6/TJP2 (tight junction protein 2)/YAP1 (Yes-associated protein 1) interacting axis and further activation of the Hippo signaling pathway. A de novo anti-CLDN6 monoclonal antibody conjugated with cytotoxic agent (Mertansine) DM1 (CLDN6-DM1) was developed. Preclinical data on both HCC cell lines and primary tumors showed the potent antitumor efficiency of CLDN6-DM1 as a single agent or in combination with sorafenib in HCC treatment.

Figures
Products