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

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.

Lineage Plasticity in Cancer: The Tale of a Skin-walker

“…Lineage plasticity has been reported to contribute to therapeutic resistance in basal cell, colorectal and hepatocellular carcinoma (HCC) as well. [143,144]. Metastatic colorectal cancer (mCRC) patients who are chemorefractory with inoperable tumors are often treated with monoclonal antibodies targeting EGFR such as cetuximab and panitumumab.…”

“…Thus, cetuximab treatment activates Paneth cell-like lineage reprogramming that results in drug tolerance in mCRC, thus underscoring the role of lineage-adapted reprogramming as a mechanism adopted by the cancer cells to evade therapy. Sorafenib, a multikinase inhibitor, is the most widely used drug for first line treatment of advanced HCC [144,149]. However, its overall survival benefit is very low [144].…”

“…Sorafenib, a multikinase inhibitor, is the most widely used drug for first line treatment of advanced HCC [144,149]. However, its overall survival benefit is very low [144]. In a recent study, Claudin 6 (CLDN6), a tight junction transmembrane protein was found to be associated with lineage plasticity which correlates with sorafenib resistance [144].…”

“…However, its overall survival benefit is very low [144]. In a recent study, Claudin 6 (CLDN6), a tight junction transmembrane protein was found to be associated with lineage plasticity which correlates with sorafenib resistance [144]. CLDN6, is highly expressed in embryonic cells but is significantly downregulated in mature hepatocytes.…”

“…It can be exploited for therapeutic purposes, as exemplified by recent studies. This could be achieved by directly inhibiting the mediators of lineage plasticity as seen in prostate cancer and basal cell carcinoma [204][205][206] or by direct targeting of the cancer cells exhibiting plasticity [144,205]. The involvement of epigenetic modulators in regulating lineage plasticity makes reversal of the plasticity another plausible therapeutic option ( [207]).…”