Dual Inhibition of EGFR and IGF-1R Signaling Leads to Enhanced Antitumor Efficacy against Esophageal Squamous Cancer.

Abstract

Both the epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) have been implicated in the development of cancers, and the increased expression of both receptors has been observed in esophageal cancer. However, the tyrosine kinase inhibitors of both receptors have thus far failed to provide clinical benefits for esophageal cancer patients. Studies have confirmed the complicated crosstalks that exist between the EGFR and IGF-1R pathways. The EGFR and IGF-1R signals act as mutual compensation pathways, thereby conveying resistance to EGFR or IGF-1R inhibitors when used alone. This study evaluated the antitumor efficacy of the EGFR/HER2 inhibitors, gefitinib and lapatinib, in combination with the IGF-1R inhibitor, linsitinib, on the esophageal squamous cell carcinoma (ESCC). Gefitinib or lapatinib, in combination with linsitinib, synergistically inhibited the proliferation, migration, and invasion of ESCC cells, caused significant cell cycle arrest, and induced marked cell apoptosis. Their combination demonstrated stronger inhibition on the activation of EGFR, HER2, and IGF-1R as well as the downstream signaling molecules. In vivo, the addition of linsitinib to gefitinib or lapatinib also potentiated the inhibition effects on the growth of xenografts. Our results suggest the next clinical exploration of the combination of gefitinib or lapatinib with linsitinib in the treatment of ESCC patients.

• Authors: Jia Kang, Zanzan Guo, Haoqi Zhang, Rongqi Guo, Xiaofei Zhu, Xiaofang Guo
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 18 (Sep 08 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 36142299 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Lapatinib
• Insulin-Like Growth Factor I
• EGFR protein, human
• ErbB Receptors
• Receptor, IGF Type 1
• Gefitinib

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation
• ErbB Receptors (metabolism)
• Esophageal Neoplasms (pathology)
• Esophageal Squamous Cell Carcinoma (drug therapy)
• Gefitinib (pharmacology, therapeutic use)
• Humans
• Insulin-Like Growth Factor I (pharmacology)
• Lapatinib (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Receptor, IGF Type 1