Human epidermal growth factor receptor 3 serves as a novel therapeutic target for acral melanoma

Abstract

Abstract Acral melanoma (AM) is a rare, life-threatening skin cancer. Since AM bears unique features, existing therapies for other types of malignant melanomas have limited effects and the establishment of effective treatments for AM is strongly desired. Human epidermal growth factor receptor 3 (HER3) is a receptor tyrosine kinase that is frequently elevated in tumors and contributes to tumor progression, so it is considered a promising therapeutic target for tumors. This study was established to evaluate the potential of HER3-targeted therapy to treat AM by investigating the expression and function of HER3 in AM. HER3 expression was immunohistochemically analyzed in AM lesions of 72 patients and the relationship between HER3 expression and patient survival was analyzed. HER3 was also measured in AM cell lines. To investigate its function, HER3 was inhibited by siRNA and its effects on cell proliferation, apoptosis/survival, anchorage-independent growth, and underlying signals were assessed. HER3 was expressed in patients’ AM tissues with various intensities. Disease-free survival was significantly shorter in HER3-positive patients than in HER3-negative ones. In vitro analyses revealed that HER3 is more highly expressed in AM cell lines than in normal epidermal melanocytes. AM cells were also shown to be sensitive to the cytotoxic part of a HER3-targeted antibody-drug conjugate. Inhibition of HER3 did not affect cell proliferation, whereas it decreased the anchorage-independent growth of AM cells. HER3 affects the nuclear translocation of Yes-associated protein (YAP) to regulate anchorage-independent growth. HER3 is expressed in AM and involved in regulating anchorage-independent growth of AM cells through YAP signaling. HER3 may thus serve as a novel therapeutic target for AM.