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Updated: May 26, 2026
Induction and Analysis of Epithelial to Mesenchymal Transition
Published on: August 27, 2013
Epithelial-mesenchymal transition predicts sensitivity to the dual IGF-1R/IR inhibitor OSI-906 in hepatocellular
Hui Zhao1, Vidhi Desai, Jian Wang
1Department of Translational Research, OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA. Hui.Zhao@us.astellas.com
Abstract:
A growing body of data indicates that inhibiting the type 1 insulin-like growth factor receptor (IGF-1R) might be an effective treatment strategy for hepatocellular carcinoma (HCC). OSI-906 is a dual IGF-1R/IR kinase inhibitor currently in phase II clinical development for HCC. However, biomarkers are lacking to help identify patients with HCC who are more likely to benefit from OSI-906 treatment. We sought to determine the effect of OSI-906 on proliferation against a panel of 21 HCC cell lines and to investigate molecular determinants of responsiveness to OSI-906. We identified a subset of HCC cell lines that was sensitive to OSI-906, and sensitivity is associated with elevated phosphorylation levels of IGF-1R and IR and greater inhibition of AKT signaling. Dual targeting of both receptors seems to be important for maximal inhibition as treatment with a selective IGF-1R-neutralizing antibody was associated with increased IR signaling, whereas OSI-906 fully inhibited both phosphorylated IR and IGF-1R and resulted in greater inhibition of the IRS/AKT pathway. Epithelial-mesenchymal transition (EMT) seems to predict HCC cell sensitivity to OSI-906, as the epithelial phenotype is strongly associated with expression of IGF-2 and IR, activation of IGF-1R and IR, and sensitivity to OSI-906, alone or in combination with erlotinib. Induction of EMT upon treatment with TGFβ reduced sensitivity to OSI-906. Collectively, these data support the concept for dual IGF-1R/IR targeting in HCC, where EMT status and expressions of IGF-2 and IR may be used to identify those patients who are most likely to benefit from treatment with an IGF-1R/IR dual inhibitor.
Insights
Dual targeting of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) with OSI-906 shows promise for hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) status and IGF-2/IR expression may predict patient response to this therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) treatment can be advanced by targeting the type 1 insulin-like growth factor receptor (IGF-1R).
- OSI-906, a dual IGF-1R/IR kinase inhibitor, is in Phase II clinical trials for HCC, but predictive biomarkers are needed.
- Identifying patients likely to respond to OSI-906 is crucial for effective HCC therapy.
Purpose of the Study:
- To evaluate the effect of OSI-906 on HCC cell proliferation and identify molecular predictors of sensitivity.
- To investigate the role of dual IGF-1R/IR inhibition in HCC treatment response.
- To explore the association between epithelial-mesenchymal transition (EMT) and sensitivity to OSI-906.
Main Methods:
- Assessed OSI-906's antiproliferative effects on 21 HCC cell lines.
- Analyzed phosphorylation levels of IGF-1R and IR, and AKT signaling pathway activity.
- Correlated epithelial-mesenchymal transition (EMT) status with IGF-2 and IR expression and OSI-906 sensitivity.
Main Results:
- A subset of HCC cell lines demonstrated sensitivity to OSI-906, linked to higher IGF-1R/IR phosphorylation and AKT inhibition.
- Dual inhibition by OSI-906 was more effective than selective IGF-1R blockade, fully inhibiting both receptors and enhancing IRS/AKT pathway inhibition.
- Epithelial phenotype, associated with IGF-2 and IR expression, predicted sensitivity to OSI-906, while EMT induction reduced sensitivity.
Conclusions:
- Dual IGF-1R/IR targeting is a viable strategy for HCC treatment.
- EMT status and expression levels of IGF-2 and IR can serve as biomarkers to identify HCC patients who may benefit from OSI-906.
- Further research into EMT and IGF signaling pathways could optimize targeted therapies for HCC.
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