Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1

Abstract

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.

Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia

“…Co-immunoprecipitation revealed that midostaurin treatment reduced Mcl-1 binding to Bim, but increased Bim binding to Bcl-2, in both MOLM-13 and MV4-11 cells. Consistent with our published work (10,11,28), venetoclax treatment reduced Bcl-2 binding to Bim, but increased binding of Mcl-1 to Bim (Figure 3C). In the combined treatment, both Mcl-1 and Bcl-2 binding to Bim were reduced.…”

Targeting nuclear import and export in hematological malignancies

“…Venetoclax treatment reduces the interaction of the proapoptotic protein Bim with BCL-2, however the interaction of Bim with the antiapoptotic protein Mcl-1 is thought to mediate resistance to venetoclax [ 57 ]. Treatment with selinexor reduces the levels of Mcl-1, and shows a synergistic effect when combined with venetoclax in AML cells [ 58 ].…”

Targeting Bcl-2 Proteins in Acute Myeloid Leukemia

“…Here, we introduce several combinations that can reduce the MCL-1 level indirectly to circumvent the resistance. Indirect MCL-1 inhibitors include the following compounds: bromodomain extra-terminal protein inhibitors (BETis), which reduce MCL-1 and BCL-XL levels while increasing BIM levels and enhance the lethal effects of venetoclax on AML ( 97 ); cyclin-dependent kinase 9 (CDK9) inhibitors, which inhibit the transcription of MCL-1 ( 98 ); midostaurin or gilteritinib, FLT3 inhibitors that induce downregulation of MCL-1 to increase venetoclax activity ( 99 ); CUDC-907, a dual PI3K and histone deacetylase inhibitor that downregulates MCL-1, upregulates BIM, and induces DNA damage ( 100 ); MEK inhibitors ( 101 ); MDM2 inhibitors ( 102 ); PI3K inhibitors ( 103 ); and selinexor, an XPO1-selective inhibitor ( 104 ). In addition, an inhibitor of the Nedd8-activating enzyme (MLN4924) can upregulate Noxa, and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors (statins) can upregulate PUMA.…”