Irreversible inhibition of Δ16HER2 is necessary to suppress Δ16HER2-positive breast carcinomas resistant to Lapatinib

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, Roberta Galeazzi, Cristina Marchini, Augusto Amici

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)76-84
Number of pages9
JournalCancer Letters
Volume381
Issue number1
DOIs
Publication statusPublished - Oct 10 2016

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Keywords

  • Breast cancer
  • Drug resistances
  • HER2 isoform
  • Targeted therapies
  • Δ16HER2 mice

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tilio, M., Gambini, V., Wang, J., Garulli, C., Kalogris, C., Andreani, C., Bartolacci, C., Elexpuru Zabaleta, M., Pietrella, L., Hysi, A., Iezzi, M., Belletti, B., Orlando, F., Provinciali, M., Galeazzi, R., Marchini, C., & Amici, A. (2016). Irreversible inhibition of Δ16HER2 is necessary to suppress Δ16HER2-positive breast carcinomas resistant to Lapatinib. Cancer Letters, 381(1), 76-84. https://doi.org/10.1016/j.canlet.2016.07.028