TY - JOUR
T1 - NECTIN4
T2 - A novel therapeutic target for melanoma
AU - Tanaka, Yuka
AU - Murata, Maho
AU - Shen, Che Hung
AU - Furue, Masutaka
AU - Ito, Takamichi
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/1/2
Y1 - 2021/1/2
N2 - 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.
AB - 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.
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U2 - 10.3390/ijms22020976
DO - 10.3390/ijms22020976
M3 - Article
C2 - 33478111
AN - SCOPUS:85100186748
SN - 1661-6596
VL - 22
SP - 1
EP - 17
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 2
M1 - 976
ER -
