The antiapoptotic Bcl-2 family proteins play critical roles in resistance to chemotherapy in acute myeloid leukaemia (AML). The Bcl-2-selective inhibitor ABT-199 (Venetoclax) shows promising antileukaemic activity against AML, though Mcl-1 limits its antileukaemic activity. XPO1 is a nuclear exporter overexpressed in AML cells and its inhibition decreases Mcl-1 levels in cancer cells. Thus, we hypothesized that the XPO1-selective inhibitor KPT-330 (Selinexor) can synergize with ABT-199 to induce apoptosis in AML cells through down-regulation of Mcl-1. The combination of KPT-330 and ABT-199 was found to synergistically induce apoptosis in AML cell lines and primary patient samples and cooperatively inhibit colony formation capacity of primary AML cells. KPT-330 treatment decreased Mcl-1 protein after apoptosis initiation. However, binding of Bim to Mcl-1 induced by ABT-199 was abrogated by KPT-330 at the same time as apoptosis initiation. KPT-330 treatment increased binding of Bcl-2 to Bim but was overcome by ABT-199 treatment, demonstrating that KPT-330 and ABT-199 reciprocally overcome apoptosis resistance. Mcl-1 knockdown and overexpression confirmed its critical role in the antileukaemic activity of the combination. In summary, KPT-330 treatment, alone and in combination with ABT-199, modulates Mcl-1, which plays an important role in the antileukaemic activity of the combination.
CITATION STYLE
Luedtke, D. A., Su, Y., Liu, S., Edwards, H., Wang, Y., Lin, H., … Ge, Y. (2018). Inhibition of XPO1 enhances cell death induced by ABT-199 in acute myeloid leukaemia via Mcl-1. Journal of Cellular and Molecular Medicine, 22(12), 6099–6111. https://doi.org/10.1111/jcmm.13886
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