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.