Phosphorylated Insulin-Like Growth Factor 1 Receptor is Implicated in Resistance to the Cytostatic Effect of Gefitinib in Colorectal Cancer Cells

Abstract

We investigated the potential mechanisms of the uncoupling of EGFR from its downstream signals in colorectal cancer (CRC) cells. Alternative growth factor receptors and regulation of downstream pathways in different gefitinib-responsive cell lines were determined. Basal insulin-like growth factor receptor-1β (IGFR-1β) phosphorylation was undetectable or present at very low levels in highly gefitinib-responsive cell lines and was present at strikingly high levels in less responsive cell lines. Further analysis of cell lines representing the most sensitive (Lovo), moderately sensitive (HT29), and most resistant (HCT116) strains was treated with an IGFR-1 inhibitor (AG1024), gefitinib, or both, revealing that elevated IGFR-1β phosphorylation can compensate for the loss of EGFR signaling function. Increased insulin-like growth factor II expression induced by gefitinib or heterodimerization of EGFR and IGFR-1β may trigger IGFR-1β signal transduction via activation of Akt and MAPK. In addition, high levels of EGFR and IGFR-1β phosphorylation were detected in CRC tumor tissue. We also showed that gefitinib- and/or AG1024-induced cytostatic effects could be mediated by glycogen synthase kinase-3β (GSK-3β) activation. Our data suggest that the crosstalk between EGFR and IGFR-1β signaling are likely to contribute to resistance of CRC cells to gefitinib and that measurement of GSK-3β activation may present a potential biomarker for evaluating the antitumor efficacy of receptor tyrosine kinase inhibition.

A Phase I Clinical Trial and Independent Patient-Derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors

“…Indeed, preclinical evidence suggests that gefitinib can induce downstream activation of the Akt and MAPK pathways in colorectal cancer cell lines by triggering phosphorylation of IGF-1R or heterodimerization of EGFR and IGF-1R (15). In a separate study, combined downregulation of both EGFR and IGF-1R in colorectal cancer cell lines was shown to decrease cell proliferation and induce apoptosis more effectively than downregulation of either receptor alone (16).…”

“…IGF-1R has also been implicated in the development of colorectal cancer (13,14), and it has been suggested that cross-talk between the EGFR and IGF-1R signaling pathways may be a mechanism by which colorectal cancer cells develop resistance to EGFR tyrosine kinase inhibitors (15). Indeed, preclinical evidence suggests that gefitinib can induce downstream activation of the Akt and MAPK pathways in colorectal cancer cell lines by triggering phosphorylation of IGF-1R or heterodimerization of EGFR and IGF-1R (15).…”

Cetuximab-Induced MET Activation Acts as a Novel Resistance Mechanism in Colon Cancer Cells

“…Sometimes, the induced activation of signaling pathway by targeted drug will drive resistance. In EGFR TKI erlotinib-resistant lung cancer cells and colon cancer cells, the induced insulin-like growth factor-I receptor activation is implicated in resistance to erlotinib [12,13]. However, whether the induced MET activation by EGFR inhibitors mediating resistance is less understood.…”

Targeting Quiescent Tumor Cells via Oxygen and IGF-I Supplementation

“…HT29 cells express a 3-fold higher level of e-cadherin, a driver of contact inhibition of proliferation (36). HT29 cells have also been shown to be more resistant than HCT116 cells to strategies that use IGF-I receptor inhibition to control tumor cell growth (37). When grown as solid tumors, both cell types exhibited regions of chronic hypoxia in areas 100 to 150 mm from vessels, and both displayed a reduction in proliferation with distance from blood vessels.…”