Activated d16HER2 homodimers and src kinase mediate optimal efficacy for trastuzumab

Lorenzo Castagnoli, Manuela Iezzi, Gaia C. Ghedini, Valentina Ciravolo, Giulia Marzano, Alessia Lamolinara, Roberta Zappasodi, Patrizia Gasparini, Manuela Campiglio, Augusto Amici, Claudia Chiodoni, Arianna Palladini, Pier Luigi Lollini, Tiziana Triulzi, Sylvie Menard, Patrizia Nanni, Elda Tagliabue, Serenella M. Pupa

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Abstract

A splice isoform of the HER2 receptor that lacks exon 16 (d16HER2) is expressed in many HER2-positive breast tumors, where it has been linked with resistance to the HER2-targeting antibody trastuzumab, but the impact of d16HER2 on tumor pathobiology and therapeutic response remains uncertain. Here, we provide genetic evidence in transgenic mice that expression of d16HER2 is sufficient to accelerate mammary tumorigenesis and improve the response to trastuzumab. A comparative analysis of effector signaling pathways activated by d16HER2 and wild-type HER2 revealed that d16HER2 was optimally functional through a link to SRC activation (pSRC). Clinically, HER2-positive breast cancers from patients who received trastuzumab exhibited a positive correlation in d16HER2 and pSRC abundance, consistent with the mouse genetic results. Moreover, patients expressing high pSRC or an activated "d16HER2 metagene" were found to derive the greatest benefit from trastuzumab treatment. Overall, our results establish the d16HER2 signaling axis as a signature for decreased risk of relapse after trastuzumab treatment.

Original languageEnglish
Pages (from-to)6248-6259
Number of pages12
JournalCancer Research
Volume74
Issue number21
DOIs
Publication statusPublished - Nov 1 2014

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Castagnoli, L., Iezzi, M., Ghedini, G. C., Ciravolo, V., Marzano, G., Lamolinara, A., Zappasodi, R., Gasparini, P., Campiglio, M., Amici, A., Chiodoni, C., Palladini, A., Lollini, P. L., Triulzi, T., Menard, S., Nanni, P., Tagliabue, E., & Pupa, S. M. (2014). Activated d16HER2 homodimers and src kinase mediate optimal efficacy for trastuzumab. Cancer Research, 74(21), 6248-6259. https://doi.org/10.1158/0008-5472.CAN-14-0983