Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10899271 | Cancer Letters | 2016 | 9 Pages |
Abstract
HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Î16HER2 splice variant commonly coexpressed with HER2 and identified as a clinically important HER2 molecular alteration promoting aggressive metastatic breast cancer. Consistently, mice transgenic for the human Î16HER2 isoform (Î16HER2 mice) develop invasive mammary carcinomas with early onset and 100% penetrance. The present study provides preclinical evidence that Î16HER2 expression confers de novo resistance to standard anti-HER2-therapies such as Lapatinib and acquired resistance to the selective Src inhibitor Saracatinib in breast cancer. Of note, Dacomitinib, an irreversible small molecule pan-HER inhibitor, was able to completely suppress Î16HER2-driven breast carcinogenesis. Thus, only Dacomitinib may offer benefit in this molecularly defined patient subset by irreversibly inhibiting Î16HER2 activation.
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Authors
Martina Tilio, Valentina Gambini, Junbiao Wang, Chiara Garulli, Cristina Kalogris, Cristina Andreani, Caterina Bartolacci, Maria Elexpuru Zabaleta, Lucia Pietrella, Albana Hysi, Manuela Iezzi, Barbara Belletti, Fiorenza Orlando, Mauro Provinciali,