Endocytic degradation of ErbB2 mediates the effectiveness of neratinib in the suppression of ErbB2-positive ovarian cancer
•An alternative way to suppress ErbB2 in ErbB2-positive ovarian cancer by lapatinib and neratinib.•This study provides specific in vitro and in vivo effects of neratinib in ErbB2-positive ovarian cancer.•Neratinib causes endosomal/lysosomal degradation of ErbB2 by inducing ubiquitylation. The tyrosi...
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Veröffentlicht in: | The international journal of biochemistry & cell biology 2019-12, Vol.117, p.105640-105640, Article 105640 |
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Sprache: | eng |
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Zusammenfassung: | •An alternative way to suppress ErbB2 in ErbB2-positive ovarian cancer by lapatinib and neratinib.•This study provides specific in vitro and in vivo effects of neratinib in ErbB2-positive ovarian cancer.•Neratinib causes endosomal/lysosomal degradation of ErbB2 by inducing ubiquitylation.
The tyrosine kinase receptor ErbB2 is frequently found to be overexpressed in multiple cancer types. Targeted therapeutic approaches against ErbB2 have shown promising results and received FDA approvals in the treatment of breast cancer. However, this approach has not been granted in ovarian cancers till now. In order to assess the validity of ErbB2-targeted therapy in ovarian cancer, we investigated the effectiveness of two FDA-approved tyrosine kinase inhibitors of ErbB2, lapatinib and neratinib, on the growth of ovarian cancers. We observed that both lapatinib and neratinib displayed inhibitory effects towards the proliferation and migration of ErbB2-positive ovarian cancer cells in vitro, with neratinib showing stronger suppression in general. Neratinib treatment led to the reduction of ErbB2 protein levels, with concomitant attenuation of the phosphorylation of AKT, MEK, and ERK1/2. Immunofluorescence assays revealed that neratinib induced the internalization and lysosomal degradation of ErbB2, which was accompanied by its hyperubiquitylation. Lapatinib and neratinib also repressed the in vivo growth of SKOV3 cells, and neratinib downregulated ErbB2 levels in xenograft tumors to cause potent inhibition. Therefore, the ubiquitylation-mediated endocytic degradation of ErbB2 incurred by neratinib treatment conferred potent inhibition of ovarian cancer growth. Clinical investigations of neratinib in ErbB2-positive ovarian cancer are warranted. |
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ISSN: | 1357-2725 1878-5875 |
DOI: | 10.1016/j.biocel.2019.105640 |