Journal
CANCER LETTERS
Volume 381, Issue 1, Pages 76-84Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2016.07.028
Keywords
HER2 isoform; Breast cancer; Delta 16HER2 mice; Targeted therapies; Drug resistances
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Funding
- Italian Association for Cancer Research (AIRC) [IG11889]
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HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Delta 16HER2 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 Delta 16HER2 isoform (Delta 16HER2 mice) develop invasive mammary carcinomas with early onset and 100% penetrance. The present study provides preclinical evidence that Delta 16HER2 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 Delta 16HER2-driven breast carcinogenesis. Thus, only Dacomitinib may offer benefit in this molecularly defined patient subset by irreversibly inhibiting Delta 16HER2 activation. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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