ABCB5-Targeted Chemoresistance Reversal Inhibits Merkel Cell Carcinoma Growth

作者：Kleffel Sonja; Lee Nayoung; Lezcano Cecilia; Wilson Brian J; Sobolewski Kristine; Saab Karim R; Mueller Hansgeorg; Zhan Qian; Posch Christian; Elco Christopher P; DoRosario Andrew; Garcia Sarah S; Thakuria Manisha; Wang Yaoyu E; Wang Linda C; Murphy George F; Frank Markus H^*; Schatton Tobias^*

来源：Journal of Investigative Dermatology, 2016, 136(4): 838-846.

DOI：10.1016/j.jid.2015.12.038

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 ABCB5 blockade can inhibit human MCC tumor growth through sensitization to drug-induced cell cytotoxicity. ABCB5 expression was detected in both established MCC lines and clinical MCC specimens at levels significantly higher than those in normal skin. Carboplatinand etoposide-resistant MCC cell lines exhibited increased expression of ABCB5, along with enhanced ABCB1 and ABCC3 transcript expression. ABCB5-expressing MCC cells in heterogeneous cancers preferentially survived treatment with carboplatin and etoposide in vitro and in human MCC xenograft-bearing mice in vivo. Moreover, patients with MCC also exhibited enhanced ABCB5 positivity after carboplatin-and etoposide-based chemotherapy, pointing to clinical significance of this chemoresistance mechanism. Importantly, ABCB5 blockade reversed MCC drug resistance and impaired tumor growth in xenotransplantation models in vivo. Our results establish ABCB5 as a chemoresistance mechanism in MCC and suggest utility of this molecular target for improved MCC therapy.

• 出版日期2016-4
• 单位河北医科大学