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Differential regulation of sunitinib targets predicts its tumor-type-specific effect on endothelial and/or tumor cell apoptosis

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Abstract

Purpose

Sunitinib is an inhibitor of tyrosine-kinase receptors, and no biomarker predictive of sunitinib response is available. The purpose of this preclinical study was to show whether sunitinib molecular targets could be used as biomarkers to assess tumor response to sunitinib in human cancer cell line xenografts of three different tumor types.

Methods

Using mice xenografted with liver, breast and renal carcinoma cell lines, we sequentially analyzed the effect of 7-day sunitinib treatment on tumor and vascular compartments.

Results

In all xenografts, microvessel damage occurred from Day 1. Tumor damage also occurred in liver, breast, but not in renal xenografts. Using specific human and mouse probes for genes encoding sunitinib targets, we showed a significant relation between apoptotic tumor cell numbers and human PDGFRΒ and RET mRNA expression in liver cancer and to human VEGFR2 expression in breast cancer xenografts. In contrast, in renal cancer xenografts, vascular effect evaluated by measuring endothelial cell apoptosis was related to mouse Vegfr1, Vegfr2 and Vegfa-164 expression.

Conclusion

This study identifies sunitinib vascular and tumor effects according to different tumor types and shows that sunitinib molecular targets used as biomarkers enable assessment of therapeutic response.

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Acknowledgments

We thank C.Dosquet for critical review of the manuscript, S.Lefrançois and S.Arien for electron microscopy techniques. Ms A.Swaine reviewed the English language. This study was supported by grants from University-Paris-Diderot, Inserm, Agence Nationale pour la Recherche (ANR), and Canceropole—Institut National du Cancer (InCa).

Conflict of interest

None.

Author information

Author notes

  1. Li Wang

    Present address: Shanghai Institute of Haematology, Shanghai, China

Authors and Affiliations

  1. Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S728, Université Paris Diderot, 75010, Paris, France

    Guilhem Bousquet, Mariana Varna, Irmine Ferreira, Li Wang, Christophe Leboeuf, Cédric de Bazelaire, Sandrine Faivre, Philippe Bertheau, Eric Raymond & Anne Janin

  2. INSERM, U728, 75010, Paris, France

    Guilhem Bousquet, Mariana Varna, Irmine Ferreira, Li Wang, Christophe Leboeuf, Cédric de Bazelaire, Sandrine Faivre, Philippe Bertheau, Eric Raymond & Anne Janin

  3. Pathologie, AP-HP-Hôpital Saint-Louis, 75010, Paris, France

    Philippe Bertheau, Stéphane Germain & Anne Janin

  4. Oncologie Médicale, AP-HP-Hôpital Saint-Louis, 75010, Paris, France

    Guilhem Bousquet

  5. Urologie, AP-HP-Hôpital Saint-Louis, 75010, Paris, France

    Pierre Mongiat-Artus

  6. Radiologie, APHP-Hôpital Saint-Louis, 75010, Paris, France

    Cédric de Bazelaire

  7. Center for Interdisciplinary Research in Biology (CIRB), Collège de France, 75005, Paris, France

    Stéphane Germain

  8. INSERM UMR-S728, Laboratoire de Pathologie, Hôpital Saint-Louis, Université Paris 7, 1 Claude Vellefaux, 75010, Paris, France

    Anne Janin

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  1. Guilhem Bousquet
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  2. Mariana Varna
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Corresponding author

Correspondence to Anne Janin.

Additional information

Guilhem Bousquet and Mariana Varna have contributed equally to this work.

Stéphane Germain and Anne Janin are equally senor authors.

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Bousquet, G., Varna, M., Ferreira, I. et al. Differential regulation of sunitinib targets predicts its tumor-type-specific effect on endothelial and/or tumor cell apoptosis. Cancer Chemother Pharmacol 72, 1183–1193 (2013). https://doi.org/10.1007/s00280-013-2300-0

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