Targeting the insulin-like growth factor-1 receptor to overcome imatinib resistance in chronic myeloid leukemia

Abstract

Abstract Patients with chronic myeloid leukemia (CML) frequently develop resistance to tyrosine kinase inhibitors such as imatinib. In this study, we explored the role of the insulin-like growth factor 1 (IGF-1) signaling pathway in CML and imatinib resistance. An analysis of IGF-1 gene expression using public databases revealed elevated levels of insulin-like growth factor-binding proteins in patients with chronic-phase CML. Further research revealed that IGF-1-related genes were upregulated in patients who were unresponsive to imatinib, suggesting that IGF-1 signaling plays a role in the resistance mechanism. Furthermore, we evaluated the efficacy of linsitinib, a selective insulin-like growth factor-1 receptor (IGF-1R) inhibitor, in inhibiting the growth of CML cell lines, including imatinib-resistant cell lines, and observed a notable decrease in cell viability and an increase in cytotoxicity. The combination of imatinib and linsitinib reduced cell viability and increased caspase-3/7 activity in imatinib-resistant cells. Moreover, silencing of IGF-1R by small interfering ribonucleic acid increased the sensitivity of CML cell lines to imatinib, indicating that IGF-1R could be a strategic target for overcoming resistance. These findings highlight the therapeutic potential of linsitinib and that IGF-1R inhibition may improve the treatment outcomes of patients with imatinib-resistant CML.

Keywords

• Chronic myeloid leukemia
• Imatinib resistance
• Insulin-like growth factor -1 receptor inhibitor