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ABCB5-Targeted Chemoresistance Reversal Inhibits Merkel Cell Carcinoma Growth
Sonja Kleffel1, Nayoung Lee1, Cecilia Lezcano2
1Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
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. Carboplatin- and 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.
Insights
Merkel cell carcinoma (MCC) drug resistance is linked to ATP-binding cassette member B5 (ABCB5). Blocking ABCB5 can resensitize MCC tumors to chemotherapy, offering a new therapeutic strategy for this aggressive skin cancer.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer.
- Chemotherapy resistance significantly limits effective MCC treatment.
- The mechanisms underlying MCC chemoresistance are not fully understood.
Purpose of the Study:
- To investigate the role of ATP-binding cassette member B5 (ABCB5) in MCC chemoresistance.
- To evaluate ABCB5 as a potential therapeutic target for overcoming drug resistance in MCC.
- To demonstrate the efficacy of ABCB5 blockade in combination with chemotherapy.
Main Methods:
- Analysis of ABCB5 expression in MCC cell lines and clinical specimens.
- Assessment of MCC cell survival and tumor growth in vitro and in vivo under chemotherapy treatment.
- Evaluation of ABCB5 blockade effects on drug sensitivity and tumor progression in MCC xenograft models.
Main Results:
- ABCB5 expression is significantly elevated in MCC compared to normal skin and is further upregulated in chemoresistant MCC cells.
- ABCB5-expressing MCC cells exhibit preferential survival during carboplatin and etoposide treatment.
- ABCB5 blockade reverses drug resistance and inhibits MCC tumor growth in preclinical models.
- Increased ABCB5 positivity in patients post-chemotherapy suggests clinical relevance.
Conclusions:
- ABCB5 is a key mechanism conferring chemoresistance in Merkel cell carcinoma.
- Targeting ABCB5 represents a promising strategy to enhance chemotherapy efficacy and improve outcomes for MCC patients.
- ABCB5 blockade can overcome established drug resistance in MCC, offering a novel therapeutic avenue.
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