In a study exploring the mechanisms of stabilized disease vs tumor regression with targeted anti–epidermal growth factor receptor (EGFR) therapy in colorectal cancer reported in Science Translational Medicine, Zanella and colleagues found that stable disease as response was characterized by overexpression of insulin growth factor (IGF) 2.
Studies in patient-derived xenografts from samples that did not harbor established resistance mutations showed that those from patients responding to cetuximab (Erbitux) with disease stabilization exhibited high levels of EGFR family ligands and receptors. Of 21 stabilized disease models with particularly high expression of EGFR and EGFR family members, 5 (24%) had tumor regression after intensified EGFR blockade with cetuximab and a small-molecule inhibitor. Of 16 models in which enhanced EGFR inhibition did not result in tumor regression, 6 (37.5%) exhibited marked overexpression of IGF2.
Enrichment of IGF2 overexpression in cases with stabilized disease was demonstrated in the entire set of patient-derived xenografts and was confirmed in colorectal cancer patients using clinical gene-expression data sets. In functional studies, IGF2 overproduction reduced the efficacy of cetuximab, and abrogation of IGF2-dependent signaling in IGF2-overexpressing models potentiated the effects of cetuximab.
The investigators concluded: “The clinical implementation of IGF inhibitors awaits reliable predictors of response, but the results of this study suggest rational combination therapies for colorectal cancer and provide evidence for IGF2 as a biomarker of reduced tumor sensitivity to anti-EGFR therapy and a determinant of response to combined IGF2/EGFR targeting.” ■
Zanella ER, et al: Sci Transl Med 7:272ra12, 2015.