Simvastatin potentiates the cell-killing activity of imatinib in imatinib-resistant chronic myeloid leukemia cells mainly through PI3K/AKT pathway attenuation and Myc downregulation

Constitutively activated BCR-ABL kinase is considered the driver event responsible in the initiation and development of chronic myeloid leukemia (CML). The advent of the first BCR-ABL inhibitor imatinib has significantly improved the clinical outcome of CML cases. However, resistance to imatinib occurs in 25-30% of CML patients. Due to the lack of effective therapeutic strategies, novel treatment approaches are urgently required for imatinibresistant CML. Simvastatin, a well-known HMG-CoA reductase inhibitor that confers tremendous clinical benefits in cardiovascular diseases, has attracted mounting attentions for its potent antitumor effects on multiple tumor types. In this study, we demonstrated that simvastatin monotherapy was effective in diminishing cell viability in both imatinib-sensitive and imatinib-resistant CML cells, including T351I mutated cells, with the latter being less vulnerable to the simvastatin than the former. Notably, we found that simvastatin acted as a robust cytotoxic sensitizer of imatinib to kill imatinib-resistant and T315I mutated CML cells in vitro and in vivo. Mechanistically, the cooperative interaction of simvastatin and imatinib was associated with the inactivation of the PI3K/Akt signaling pathway, which was a classical downstream pro-survival cascade of the BCR-ABL kinase. In addition, this drug combination obviously decreased Myc expression through attenuation of canonical Wnt/beta-catenin signaling and increased H3K27 trimethylation. Taken together, we provide attractive preclinical results for the combinatorial regimen of simvastatin and imatinib against imatinib-resistant and T315I mutated CML cells. This combined regimens warrants further clinical investigations in patients with imatinib-resistant CML.

Automated summary

Constitutively activated BCR-ABL kinase is the driver event in chronic myeloid leukemia (CML) development. Imatinib, the first BCR-ABL inhibitor, has improved clinical outcomes, but resistance occurs in 25-30% of patients. Simvastatin, a HMG-CoA reductase inhibitor, shows antitumor effects and acts as a sensitizer to kill imatinib-resistant and T315I mutated CML cells.