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HER-targeted tyrosine kinase inhibitors enhance response to trastuzumab and pertuzumab in HER2-positive breast cancer

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Summary

Despite trastuzumab and pertuzumab improving outcome for patients with HER2-positive metastatic breast cancer, the disease remains fatal for the majority of patients. This study evaluated the anti-proliferative effects of adding anti-HER2 tyrosine kinase inhibitors (TKIs) to trastuzumab and pertuzumab in HER2-positive breast cancer cells. Afatinib was tested alone and in combination with trastuzumab in HER2-positive breast cancer cell lines. TKIs (lapatinib, neratinib, afatinib) combined with trastuzumab and/or pertuzumab were tested in 3 cell lines, with/without amphiregulin and heregulin-1β. Seven of 11 HER2-positive cell lines tested were sensitive to afatinib (IC50 < 80 nM). Afatinib plus trastuzumab produced synergistic growth inhibition in eight cell lines. In trastuzumab-sensitive SKBR3 cells, the TKIs enhanced response to trastuzumab. Pertuzumab alone did not inhibit growth and did not enhance trastuzumab-induced growth inhibition or antibody-dependent cellular cytotoxicity. Pertuzumab enhanced response to trastuzumab when combined with lapatinib but not neratinib or afatinib. In two trastuzumab-resistant cell lines, the TKIs inhibited growth but adding trastuzumab and/or pertuzumab did not improve response compared to TKIs alone. Amphiregulin plus heregulin-1β stimulated proliferation of SKBR3 and MDA-MB-453 cells. In the presence of the growth factors, neither antibody inhibited growth and the TKIs showed significantly reduced activity. The triple combination of trastuzumab, pertuzumab and a TKI showed the strongest anti-proliferative activity in all three cell lines, in the presence of exogenous growth factors. In summary, addition of anti-HER2 TKIs to combined anti-HER2 monoclonal antibody therapy results in enhanced anticancer activity. These data contribute to the rationale for studying maximum HER2 blockade in the clinic.

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Funding

This work was supported by the Health Research Board Clinician Scientist Award (CSA/2007/11), the Irish Research Council for Science Engineering and Technology, Science Foundation Ireland (08/SRC/B1410), the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT Grant (CCRC13GAL) and the Cancer Clinical Research Trust. “The opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the Irish Cancer Society”.

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  1. Alexandra Canonici and Laura Ivers contributed equally to this work.

Authors and Affiliations

  1. Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland

    Alexandra Canonici, Laura Ivers, Neil T. Conlon, Kasper Pedersen, Nicola Gaynor, Brigid C. Browne, Denis M. Collins, Norma O’Donovan & John Crown

  2. Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

    Neil A. O’Brien

  3. Department of Medical Oncology, St Vincent’s University Hospital, Dublin, Ireland

    Giuseppe Gullo & John Crown

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  1. Alexandra Canonici
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  2. Laura Ivers
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  3. Neil T. Conlon
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Correspondence to Norma O’Donovan.

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Conflict of interest

NOD, AC, JC received research funding from Boehringer Ingelheim. DC, JC received research funding from Roche and Puma Biotechnology. DC received research funding from Puma Biotechnology. AC received travel support to attend meetings from Boehringer Ingelheim. NOD, JC received research funding from GlaxoSmithKline. JC received speaking/advisory honoraria from GlaxoSmithKline, Boehringer Ingelheim, Roche and Puma Biotechnology. All remaining authors declare that they have no conflicts of interest.

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Canonici, A., Ivers, L., Conlon, N.T. et al. HER-targeted tyrosine kinase inhibitors enhance response to trastuzumab and pertuzumab in HER2-positive breast cancer. Invest New Drugs 37, 441–451 (2019). https://doi.org/10.1007/s10637-018-0649-y

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