Abstract
HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Δ16HER2 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 Δ16HER2 isoform (Δ16HER2 mice) develop invasive mammary carcinomas with early onset and 100% penetrance. The present study provides preclinical evidence that Δ16HER2 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 Δ16HER2-driven breast carcinogenesis. Thus, only Dacomitinib may offer benefit in this molecularly defined patient subset by irreversibly inhibiting Δ16HER2 activation.
Original language | English |
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Pages (from-to) | 76-84 |
Number of pages | 9 |
Journal | Cancer Letters |
Volume | 381 |
Issue number | 1 |
DOIs | |
Publication status | Published - Oct 10 2016 |
Keywords
- Breast cancer
- Drug resistances
- HER2 isoform
- Targeted therapies
- Δ16HER2 mice
ASJC Scopus subject areas
- Cancer Research
- Oncology