Abstract
Malignant melanoma is the most common lethal skin cancer and causes death in a short time when metastasized. Although BRAF inhibitors (BRAFi) have greatly improved the prognosis of BRAF-mutated melanoma, drug resistance is a major concern even when they are combined with MEK inhibitors. Alternative treatments for BRAFi-resistant melanoma are highly anticipated. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed and associated with progression in tumors. We aimed to investigate the role of NECTIN4 in melanoma and its potency as a therapeutic target using 126 melanoma samples and BRAFi-resistant cells. Immunohistochemically, most of the clinical samples expressed NECTIN4, at least in part. NECTIN4 was highly expressed in BRAF-mutated melanoma and its high expression was associated with disease-free survival. In BRAFi-resistant melanoma cells, NECTIN4 and the PI3K/Akt pathway were upregulated, along with the acquisition of BRAFi resistance. Monomethyl auristatin E, a cytotoxic part of NECTIN4-targeted antibody–drug conjugate, was effective for BRAF-mutated or BRAFi-resistant melanoma cells. NECTIN4 inhibition increased the sensitivity of BRAFi-resistant cells to BRAFi and induced apoptosis. In conclusion, we revealed the expression and roles of NECTIN4 in melanoma. Targeted therapies against NECTIN4 can be a novel treatment strategy for melanoma, even after the acquisition of BRAFi resistance.
Highlights
Malignant melanoma is one of the most common lethal skin cancers, arising from melanocytes
NECTIN4 was significantly increased in MEL1617-DR and SKMEL28-DR compared with their drugsensitive counterparts. These results show that NECTIN4 is expressed in melanoma cells and that its expression is upregulated in BRAF inhibitors (BRAFi)-resistant cells
Since NECTIN4 was upregulated in the BRAFiresistant cells, we investigated whether the PI3K/Akt pathway is activated or not
Summary
Malignant melanoma is one of the most common lethal skin cancers, arising from melanocytes. The incidence of melanoma has been increasing worldwide and the estimated annual increase in its incidence is approximately 3–7% for Caucasians [1,2,3]. Localized melanomas can be treated by surgical excision (5-year survival rate > 90%), melanoma frequently becomes invasive and metastasizes. Dacarbazine-based chemotherapy or radiation therapy used to be applied for unresectable melanoma, but the efficacy was low (survival rate < 10%) [4,5]. Immune checkpoint inhibitors (ICI), such as PD-1 inhibitors (nivolumab, pembrolizumab) and a CTLA4 inhibitor (ipilimumab), have been applied for the treatment of advanced melanoma, which dramatically improved the prognosis of patients [6,7]
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