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An antibody to amphiregulin, an abundant growth factor in patients’ fluids, inhibits ovarian tumors

Oncogene volume 35, pages 438–447 (2016)Cite this article

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Abstract

Growth factors of the epidermal growth factor (EGF)/neuregulin family are involved in tumor progression and, accordingly, antibodies that intercept a cognate receptor, epidermal growth factor receptor (EGFR)/ERBB1, or a co-receptor, HER2, have been approved for cancer therapy. Although they might improve safety and delay onset of chemoresistance, no anti-ligand antibodies have been clinically approved. To identify suitable ligands, we surveyed fluids from ovarian and lung cancer patients and found that amphiregulin (AREG) is the most abundant and generalized ligand secreted by advanced tumors. AREG is a low affinity EGFR ligand, which is upregulated following treatment with chemotherapeutic drugs. Because AREG depletion retarded growth of xenografted ovarian tumors in mice, we generated a neutralizing monoclonal anti-AREG antibody. The antibody inhibited growth of ovarian cancer xenografts and strongly enhanced chemotherapy efficacy. Taken together, these results raise the possibility that AREG and other low- or high-affinity binders of EGFR might serve as potential targets for cancer therapy.

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Acknowledgements

We thank Julian Downward for lung cell lines. This work was performed at the Marvin Tanner Laboratory for Cancer Research and it was supported, in part, by Merck KGaA. The research in our laboratory is supported by the Israel Cancer Research Fund and the Dr Miriam and Sheldon G Adelson Medical Research Foundation and by the MD Moross Institute for Cancer Research. YY is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. The Sheba Institutional Tissue Banks have received financial support from the Flight Attendants Medical Research Institute (FAMRI).

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Author notes

  1. S Carvalho, M Lindzen & M Lauriola

    Present address: 9Current address: Unit of Histology, Embryology and Applied Biology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40126, Italy.,

  2. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    S Carvalho, M Lindzen, M Lauriola, N Shirazi, S Sinha & Y Yarden

  2. Kaplan Medical Center, Rehovot, Israel

    A Abdul-Hai

  3. The Dr. Pinchas Borenstein Talpiot Medical Leadership Program and Institute of Oncology, The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel

    K Levanon

  4. Department of Gynecologic Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel

    J Korach

  5. Department of Pathology, Sheba Medical Center, Ramat Gan, Israel

    I Barshack

  6. Institutional Tissue Banks, Sheba Medical Center, Ramat Gan, Israel

    Y Cohen

  7. Institute of Pulmonary Oncology, Chaim Sheba Medical Center Ramat Gan, Israel

    A Onn

  8. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G Mills

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Correspondence to Y Yarden.

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Carvalho, S., Lindzen, M., Lauriola, M. et al. An antibody to amphiregulin, an abundant growth factor in patients’ fluids, inhibits ovarian tumors. Oncogene 35, 438–447 (2016). https://doi.org/10.1038/onc.2015.93

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  • DOI: https://doi.org/10.1038/onc.2015.93

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