Peptide-based inhibition of CD44v6 renders liver carcinomas more susceptible to therapeutic intervention.

Cluster of differentiation 44 variant 6 (CD44v6) has been described in various types of cancer, including liver cancer. Despite significant advancements in cancer therapy, there is still an urgent medical need for new therapeutic strategies for the treatment of liver tumours that are efficacious but well tolerated. One promising approach involves the use of small molecules, such as peptides, which intervene in central signalling pathways to prevent the migration of cancer cells and their invasion into other organs without affecting other cell types. We analysed the expression of CD44v6 in human cirrhotic livers, liver tumour tissues and organoids as well as in preclinical models of chronic liver disease and subsequent liver tumour formation. We overexpressed CD44v6 in CD44v6-negative cell lines to assess its impact on the functionality of cancer cells. Furthermore, we used AMC303, a peptide inhibitor that specifically binds to CD44v6, to investigate the consequences of CD44v6 inhibition in liver cancer and its impact on combination therapies. We demonstrated that CD44v6 is expressed in chronic liver conditions, and is overexpressed in liver cancer, where it serves as a cancer stem cell marker. We also established that CD44v6 influences migration and stemness in liver cancer, and its overexpression triggers an altered gene expression pattern including increased EMT and stemness signatures. Notably, we were able to increase the efficacy of TKI/chemotherapeutics by inhibiting CD44v6. In summary, inhibition of CD44v6 renders liver carcinomas more susceptible to therapeutic intervention, thereby representing a promising target for cotreatment strategies. KEY MESSAGES: CD44v6 is expressed in chronic liver disease and is overexpressed in liver cancer. CD44v6 has been demonstrated to exert a significant influence on the processes of migration and stemness in liver cancer. Overexpression of CD44v6 triggers an altered gene expression pattern, characterized by an increase in EMT and stemness signatures. Inhibition of CD44v6 increases the efficacy of TKI/chemotherapeutics in cell lines and organoids generated from liver carcinoma. CD44v6 inhibition renders liver carcinomas more susceptible to therapeutic intervention, thereby representing a promising target for cotreatment strategies.