NECTIN4: A novel therapeutic target for melanoma

Yuka Tanaka, Maho Murata, Che Hung Shen, Masutaka Furue, Takamichi Ito

Research output: Contribution to journalArticlepeer-review

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. Nec-tin cell adhesion molecule 4 (NECTIN4) is highly expressed and associated with progression in tu-mors. 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 apop-tosis. In conclusion, we revealed the expression and roles of NECTIN4 in melanoma. Targeted ther-apies against NECTIN4 can be a novel treatment strategy for melanoma, even after the acquisition of BRAFi resistance.

Original languageEnglish
Article number976
Pages (from-to)1-17
Number of pages17
JournalInternational journal of molecular sciences
Volume22
Issue number2
DOIs
Publication statusPublished - Jan 2 2021

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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