Research ArticleCancer

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

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Science Translational Medicine  03 Feb 2021:
Vol. 13, Issue 579, eabb6282
DOI: 10.1126/scitranslmed.abb6282

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Targeting tumor lineage plasticity

Lineage plasticity allows tumor cells to evolve during anticancer treatment, resulting in therapeutic resistance. Here, Kong et al. found that claudin6 was reactivated in hepatocellular carcinoma tumor tissue and shifted cell phenotype to the biliary lineage, which was refractory to treatment with the kinase inhibitor sorafenib. Treatment with an anti-claudin6 antibody conjugated to a microtubule toxic drug killed hepatocellular carcinoma cells in vitro, in primary human tumor tissues ex vivo, and inhibited tumor growth in mouse models, with or without sorafenib treatment. Results suggest that the claudin6 antibody-drug conjugate could be therapeutic for hepatocellular carcinoma.

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.

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