Epithelial-mesenchymal transition predicts sensitivity to the dual IGF-1R/IR inhibitor OSI-906 in hepatocellular carcinoma cell lines.

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.

• Authors: Hui Zhao, Vidhi Desai, Jian Wang, David M Epstein, Mark Miglarese, Elizabeth Buck
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 2 Pg. 503-13 (Feb 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22161861 (Publication Type: Journal Article)

Chemical References

• 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
• Imidazoles
• Protein Kinase Inhibitors
• Pyrazines
• Quinazolines
• Insulin-Like Growth Factor II
• Erlotinib Hydrochloride
• Receptor, IGF Type 1
• Receptor, Insulin
• Proto-Oncogene Proteins c-akt

Topics

• Blotting, Western
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Line, Tumor
• Drug Synergism
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• Erlotinib Hydrochloride
• Gene Expression Regulation, Neoplastic (drug effects)
• Hep G2 Cells
• Humans
• Imidazoles (pharmacology)
• Insulin-Like Growth Factor II (genetics, metabolism)
• Liver Neoplasms (genetics, metabolism, pathology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrazines (pharmacology)
• Quinazolines (pharmacology)
• Receptor, IGF Type 1 (antagonists & inhibitors, genetics, metabolism)
• Receptor, Insulin (antagonists & inhibitors, genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)