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Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies

Oncogene volume 36, pages 797–806 (2017)Cite this article

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Abstract

Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 (IGF2) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2-overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody. We found that a subset of CRC cell lines express high IGF-2 levels owing to an increased DNA copy number and hypermethylation in the H19 promoter of the IGF2 gene. MEDI-573 efficiently neutralized IGF-2 and induced apoptosis, which resulted in significant tumor growth inhibition in CRC mouse models that express high levels of IGF-2. These effects were specific to CRCs overexpressing IGF-2, as MEDI-573 did not affect the growth CRC cell lines with normal levels. Moreover, blockade of IGF-2 by MEDI-573 modulated other signaling pathways, suggesting combination therapies with inhibitors of these pathways. Indeed, in vivo efficacy was significantly enhanced when MEDI-573 was used in combination with trastuzumab, AZD2014 (dual mTORC1/2i), AZD5363 (AKTi) and selumetinib (AZD6244/ARRY-142886, MEK1/2i) or cetuximab. These results demonstrate that overexpressed IGF-2 is the major tumorigenic driver in a subset of CRCs and encourage testing of MEDI-573, alone and in combinations, in IGF2-overexpressing CRC patients.

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Acknowledgements

We thank Mohammed Dar, Parthiv Mahadevia, Dirk Mendel, Robert Sikorski, Teresa Klinowska, Sabina Cosulich, Barry Davies and Stephen Green for scientific input and manuscript review. This work was supported by MedImmune.

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Authors and Affiliations

  1. Oncology Research, MedImmune, Gaithersburg, MD, USA

    H Zhong, C Fazenbaker, C Chen, S Breen, R Herbst & R E Hollingsworth

  2. Translational Science, MedImmune, Gaithersburg, MD, USA

    J Huang, X Yao & Y Yao

  3. Biostatistics, MedImmune, Gaithersburg, MD, USA

    P Ren

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Correspondence to R E Hollingsworth.

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Zhong, H., Fazenbaker, C., Chen, C. et al. Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies. Oncogene 36, 797–806 (2017). https://doi.org/10.1038/onc.2016.248

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