Chidamide, a Novel Histone Deacetylase Inhibitor, Combined with Imatinib Induces Synthetic Lethality in Drug-Resistant Chronic Myeloid Leukemia

Background and Objective

Tyrosine kinase inhibitor (TKI) resistance and progression to blast crisis (BC) remain formidable challenges for chronic myeloid leukemia (CML). The second-generation TKI have been shown to overcome Imatinib-resistance in CML, but limited effect in CML cells harboring the T315I mutation and leukemia stem cells (LSC). Histone deacetylase inhibitors (HDACi) have shown promise as a therapy for TKI-resistance cells and CML-LSC. Chidamide (CS055/HBI-8000), a novel orally active HDACi, has been approved for treatment of T-cell lymphomas in multiple clinical trials, whereas its effect on CML patients has not been characterized. Here we investigated the effects of Chidamide alone and in combination with Imatinib(IM), on isogenic TKI-sensitive and -resistant CML cell lines, as well as BC-CML stem/progenitor cells.

Methods and Results

We chosen CML cell lines (KBM5 cells and KBM5-T315I cells) and primary cells from 7 BC-CML patients and 5 healthy volunteers as experimental subject. We found that treatment with Chidamide alone inhibited cell proliferation, induced cell cycle G₀/G₁ arrest and apoptosis in Bcr-Abl expressing KBM5 cells by FCM. Co-treatment with Chidamide and Imatinib synergistically killed TKI-resistant CML cell line KBM5-T315I, and caused more reduction in phosphorylation of Bcr-Abl, STAT5 and CRKL by Western-blot, as compared with treatment with either agent alone (P <.05). Additionally, β-catenin is overexpressed in BC-CML stem/progenitor cells and can be induced by BM stromal cells, suggesting that β-catenin contributes to intrinsic and extrinsic Bcr-Abl kinase-independent TKI-resistance in CML. The co-treatment was also associated with a greater decrease in the protein levels of β-catenin, C-myc and Survivin, increase in the acetylation of Histone H3 and activation of Caspase-3/-9. Importantly, combination of Chidamide and Imatinib significantly down-regulated Bcr-Abl levels and induced apoptosis of CD34⁺ leukemia stem/progenitor cells derived from BC-CML patients with or without Bcr-Abl kinase mutations, but exhibited minimal toxicity to normal CD34⁺ progenitor cells.

Conclusion

Combined treatment with Chidamide and Imatinib exerts a superior anti-leukemia activity on CML cells including T315I mutation-harboring cell line, as well as BC-CML stem/progenitor cells. Our findings suggest potential benefit of the combination to overcome Bcr-Abl kinase-dependent and -independent TKI-resistance in CML, which may be a promising strategy to TKI-resistant BC-CML patients.