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Targeting c-Met in triple negative breast cancer: preclinical studies using the c-Met inhibitor, Cpd A

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Summary

Introduction Triple negative breast cancer (TNBC) represents a heterogeneous subtype of breast cancer that carries a poorer prognosis. There remains a need to identify novel drivers of TNBC, which may represent targets to treat the disease. c-Met overexpression is linked with decreased survival and is associated with the basal subtype of breast cancer. Cpd A, a kinase inhibitor selective/specific for Met kinase has demonstrated preclinical anti-cancer efficacy in TNBC. We aimed to assess the anti-cancer efficacy of Cpd A when combined with Src kinase, ErbB-family or hepatocyte growth factor (HGF) inhibitors in TNBC cell lines. Methods We determined the anti-proliferative effects of Cpd A, rilotumumab, neratinib and saracatinib tested alone and in combination in a panel of TNBC cells by acid phosphatase assays. We performed reverse phase protein array analysis of c-Met and IGF1Rβ expression and phosphorylation of c-Met (Y1234/1235) in TNBC cells and correlated their expression/phosphorylation with Cpd A sensitivity. We examined the impact of Cpd A, neratinib and saracatinib tested alone and in combination on invasive potential and colony formation.Results TNBC cells are not inherently sensitive to Cpd A, and neither c-Met expression nor phosphorylation are biomarkers of sensitivity to Cpd A. Cpd A enhanced the anti-proliferative effects of neratinib in vitro; however, this effect was limited to cell lines with innate sensitivity to Cpd A. Cpd A had limited anti-invasive effects but it reduced colony formation in the TNBC cell line panel.Conclusions Despite Cpd A having a potential role in reducing cancer cell metastasis, identification of strong predictive biomarkers of c-Met sensitivity would be essential to the development of a c-Met targeted treatment for an appropriately selected cohort of TNBC patients.

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Acknowledgements

We would like to acknowledge Amgen, who kindly provided access to the c-Met inhibitor Compound-A used in our studies.

Funding

This research was supported by funding from the Health Research Board (CSA/2007/11), Science Foundation Ireland (08/SRC/B1410), the Cancer Clinical Research Trust/The Caroline Foundation and the Irish Cancer Society Collaborative Cancer Research Centre Breast-Predict (CCRC13GAL). 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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Author notes

  1. Norma O’Donovan and Alex J. Eustace are joint senior authors.

Authors and Affiliations

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

    Laura Breen, Patricia B. Gaule, Alexandra Canonici, Naomi Walsh, Denis M. Collins, John Crown, Norma O’ Donovan & Alex J. Eustace

  2. Medical Oncology Group, Department of Molecular Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland

    Mattia Cremona & Bryan T. Hennessy

  3. UCD Clinical Research Centre, St. Vincent’s University Hospital, Dublin, Ireland

    Michael J. Duffy

  4. UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland

    Michael J. Duffy

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

    John Crown

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Laura Breen and Patricia B. Gaule are joint first authors.

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Breen, L., Gaule, P.B., Canonici, A. et al. Targeting c-Met in triple negative breast cancer: preclinical studies using the c-Met inhibitor, Cpd A. Invest New Drugs 38, 1365–1372 (2020). https://doi.org/10.1007/s10637-020-00937-y

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