ABCB5-Targeted Chemoresistance Reversal Inhibits Merkel Cell Carcinoma Growth

Merkel cell carcinoma(MCC) is a highly aggressive neuroendocrine skin cancer with profound but poorly understood resistance to chemotherapy, which poses a significant barrier to clinical MCC treatment. Here we show that ATP-binding cassette member B5 ( ABCB5) confers resistance to standard-of-care MCC chemotherapeutic agents and provide proof-of-principle that ABCB5blockade can inhibit human MCC tumor growth through sensitization to drug-induced cell cytotoxicity. ABCB5expression was detected in both established MCC lines and clinical MCC specimens at levels significantly higher than those in normal skin. Carboplatin- and etoposide-resistant MCC cell lines exhibited increased expression of ABCB5, along with enhanced ABCB1 and ABCC3transcript expression. ABCB5-expressing MCC cells in heterogeneous cancers preferentially survived treatment with carboplatinand etoposidein vitro and in human MCC xenograft-bearing mice in vivo. Moreover, patients with MCC also exhibited enhanced ABCB5positivity after carboplatin- and etoposide-based chemotherapy, pointing to clinical significance of this chemoresistance mechanism. Importantly, ABCB5blockade reversed MCC drug resistance and impaired tumor growth in xenotransplantationmodels in vivo. Our results establish ABCB5as a chemoresistance mechanism in MCC and suggest utility of this molecular target for improved MCC therapy.