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 |
|---|---|
| Pages (from-to) | 76-84 |
| Number of pages | 9 |
| Journal | Cancer Letters |
| Volume | 381 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 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
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, Vol. 381, No. 1, 10.10.2016, p. 76-84.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Irreversible inhibition of Δ16HER2 is necessary to suppress Δ16HER2-positive breast carcinomas resistant to Lapatinib
AU - Tilio, Martina
AU - Gambini, Valentina
AU - Wang, Junbiao
AU - Garulli, Chiara
AU - Kalogris, Cristina
AU - Andreani, Cristina
AU - Bartolacci, Caterina
AU - Elexpuru Zabaleta, Maria
AU - Pietrella, Lucia
AU - Hysi, Albana
AU - Iezzi, Manuela
AU - Belletti, Barbara
AU - Orlando, Fiorenza
AU - Provinciali, Mauro
AU - Galeazzi, Roberta
AU - Marchini, Cristina
AU - Amici, Augusto
PY - 2016/10/10
Y1 - 2016/10/10
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Drug resistances
KW - HER2 isoform
KW - Targeted therapies
KW - Δ16HER2 mice
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UR - http://www.scopus.com/inward/citedby.url?scp=84979887689&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2016.07.028
DO - 10.1016/j.canlet.2016.07.028
M3 - Article
VL - 381
SP - 76
EP - 84
JO - Cancer Letters
JF - Cancer Letters
SN - 0304-3835
IS - 1
ER -