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In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib

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Abstract

The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models. We find single-agent activity of the HER2-targeting drugs but not figitumumab in the BT474 model, while the reverse is true in the MCF7 model. However, in both models, combining figitumumab with HER2-targeting drugs shows synergistic anti-proliferative and apoptosis-inducing effects, and optimum inhibition of downstream signaling. In murine xenograft models, synergistic anti-tumor effects were observed in the HER2-normal MCF7 model for the combination of figitumumab with trastuzumab, and, in the HER2-overexpressing BT474 model, enhanced anti-tumor effects were observed for the combination of figitumumab with either trastuzumab or neratinib. Analysis of tumor extracts from the in vivo experiments showed evidence of the most optimal inhibition of downstream signaling for the drug combinations over the single-agent therapies. These results suggest promise for such combinations in treating patients with breast cancer, and that, unlike the case for single-agent therapy, the therapeutic effects of such combinations may be independent of expression levels of the individual receptors or the single-agent activity profile.

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Acknowledgments

Supported by grants from Pfizer and Connecticut Breast Health Initiative, Inc, to MPD. We thank Dr. Mark Lippman for MCF7 cells and advice on their use. We also thank the services of the animal facility of the Yale School of Medicine, and the Yale Cancer Center Flow Cytometry shared resource (supported by US Public Health Service Grant CA-16359 from the National Cancer institute) for assistance with flow cytometry.

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Authors and Affiliations

  1. Departments of Internal Medicine (Section of Medical Oncology) and Pharmacology, and The Yale Cancer Center, Yale University School of Medicine, 300 George Street, Suite 120, New Haven, CT, 06510, USA

    Ashok K. Chakraborty, Cynthia Zerillo & Michael P. DiGiovanna

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  1. Ashok K. Chakraborty
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  3. Michael P. DiGiovanna
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Correspondence to Michael P. DiGiovanna.

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Conflict of Interest

This work was supported in part by a research grant from Pfizer to MPD. MPD has received royalties from DAKO and NeoMarkers, and consulting fees from Merck. CZ and AKC declare that they do not have any financial conflicts of interest.

Ethical Approval

The experiments conducted herein comply with the current laws of the United States of America. Mice were maintained and handled in accordance with Yale Institutional Animal Care and Use Committee protocols and regulations, which also approved the research protocol. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

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Chakraborty, A.K., Zerillo, C. & DiGiovanna, M.P. In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib. Breast Cancer Res Treat 152, 533–544 (2015). https://doi.org/10.1007/s10549-015-3504-2

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