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.
|Titolo:||Irreversible inhibition of Δ16HER2 is necessary to suppress Δ16HER2- positive breast carcinomas resistant to Lapatinib|
|Data di pubblicazione:||2016|
|Citazione:||Irreversible inhibition of Δ16HER2 is necessary to suppress Δ16HER2- positive breast carcinomas resistant to Lapatinib / Tilio, Martina; Gambini, Valentina; Wang, Junbiao; Garulli, Chiara; Kalogris, Cristina; Andreani, Cristina; Bartolacci, Caterina; ELEXPURU ZABALETA, Maria; Pietrella, Lucia; Hysi, Albana; Iezzi, Manuela; Belletti, Barbara; Orlando, Fiorenza; Provinciali, Mauro; Galeazzi, Roberta; Marchini, Cristina; Amici, Augusto. - In: CANCER LETTERS. - ISSN 0304-3835. - STAMPA. - 381(2016), pp. 76-84.|
|Appare nelle tipologie:||Articolo|