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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
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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
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Journal Article
Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies
2017
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38/39
/ 96
/ Analysis
/ Animals
/ Antibodies, Monoclonal - immunology
/ Antibodies, Monoclonal - pharmacology
/ Cancer
/ Cells
/ Colorectal Neoplasms - genetics
/ Colorectal Neoplasms - immunology
/ Colorectal Neoplasms - pathology
/ Colorectal Neoplasms - therapy
/ Female
/ Genes
/ Genomes
/ Humans
/ Insulin
/ Insulin-like growth factor I
/ Insulin-like growth factor II
/ Insulin-Like Growth Factor II - antagonists & inhibitors
/ Insulin-Like Growth Factor II - biosynthesis
/ Insulin-Like Growth Factor II - genetics
/ Insulin-Like Growth Factor II - immunology
/ Medicine
/ Mice
/ Oncology
/ Rodents
/ Tumors
