Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 22, Issue 12, Pages 6099-6111Publisher
WILEY
DOI: 10.1111/jcmm.13886
Keywords
ABT-199; acute myeloid leukaemia; Bcl-2; KPT-330; XPO1
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Funding
- Children's Hospital of Michigan Foundation
- Hyundai Hope On Wheels
- National Natural Science Foundation of China [NSFC 31471295, NSFC 31671438]
- Kids Without Cancer
- DeRoy Testamentary Foundation
- LaFontaine Family/U Can-Cer Vive Foundation
- Ring Screw Textron Endowed Chair for Pediatric Cancer Research
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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.
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