Abstract
Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, the identification of selection biomarkers for enrichment of potential responders represents a high priority for future trials of these agents. Several reports have described high IGF2 expression in a subset of colorectal cancers, with focal IGF2 amplification being responsible for some of these cases. We defined a novel cut-off value for IGF2 overexpression based on differential expression between colorectal tumors and normal tissue samples. Analysis of two independent colorectal cancer datasets revealed IGF2 to be overexpressed at a frequency of 13% to 22%. An in vitro screen of 34 colorectal cancer cell lines revealed IGF2 expression to significantly correlate with sensitivity to the IGF1R/INSR inhibitor BI 885578. Furthermore, autocrine IGF2 constitutively activated IGF1R and Akt phosphorylation, which was inhibited by BI 885578 treatment. BI 885578 significantly delayed the growth of IGF2-high colorectal cancer xenograft tumors in mice, while combination with a VEGF-A antibody increased efficacy and induced tumor regression. Besides colorectal cancer, IGF2 overexpression was detected in more than 10% of bladder carcinoma, hepatocellular carcinoma and non-small cell lung cancer patient samples. Meanwhile, IGF2-high non-colorectal cancer cells lines displayed constitutive IGF1R phosphorylation and were sensitive to BI 885578. Our findings suggest that IGF2 may represent an attractive patient selection biomarker for IGF pathway inhibitors and that combination with VEGF-targeting agents may further improve clinical outcomes. Mol Cancer Ther; 16(10); 2223-33. ©2017 AACR.
Highlights
The ability of insulin-like growth factor-1 (IGF1) and IGF2 to potently promote proliferation and survival of diverse human cancer cell lines via activation of the IGF1R and insulin receptor-A (INSRA) suggests that agents inhibiting these factors may have therapeutic application in cancer patients [1]
Gene amplification and overexpression of the IGF1R has been described in a subset of estrogen receptor–positive breast cancers [7], non– small cell lung cancers (NSCLC; ref. 8), small-cell lung cancers (SCLC; ref. 9), and gastrointestinal stromal tumors
We examined IGF2 overexpression in colorectal cancer and other tumor types and used preclinical models of these cancers to investigate whether IGF2 expression predicts for sensitivity to the IGF1R/INSR tyrosine kinase inhibitors (TKI) BI 885578
Summary
The ability of insulin-like growth factor-1 (IGF1) and IGF2 to potently promote proliferation and survival of diverse human cancer cell lines via activation of the IGF1R and insulin receptor-A (INSRA) suggests that agents inhibiting these factors may have therapeutic application in cancer patients [1]. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Oncogenic alterations such as EGFR-activating mutations [4], HER2 amplification [5], and ALK rearrangements [6] have been clinically validated to predict for response to inhibitors of these targets. Several alterations in IGF pathway components have been identified in patient tumors or cancer models, which may represent candidate selection biomarkers. Gene amplification and overexpression of the IGF1R has been described in a subset of estrogen receptor–positive breast cancers [7], non– small cell lung cancers Several studies have identified molecular signatures that predict in vitro sensitivity of cancer cell lines to IGF pathway inhibitors [14,15,16]
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