Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia.

Venetoclax, an FDA-approved Bcl-2 selective inhibitor for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia (AML), is tolerated well in elderly patients with AML and has good overall response rates; however, resistance remains a concern. In this study, we show that targeting CDK9 with voruciclib in combination with venetoclax results in synergistic antileukemic activity against AML cell lines and primary patient samples. CDK9 inhibition enhances venetoclax activity through downregulation of Mcl-1 and c-Myc.

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

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.

Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells.

Acute myeloid leukemia (AML) is a serious disease. The 5-year survival rates remain frustratingly low (65% for children and 26% for adults). Resistance to frontline chemotherapy (usually cytarabine) often develops; therefore a new treatment modality is needed.

Mechanisms responsible for the synergistic antileukemic interactions between ATR inhibition and cytarabine in acute myeloid leukemia cells.

Acute myeloid leukemia (AML) continues to be a challenging disease to treat, thus new treatment strategies are needed. In this study, we investigated the antileukemic effects of ATR inhibition alone or combined with cytarabine in AML cells. Treatment with the ATR-selective inhibitor AZ20 caused proliferation inhibition in AML cell lines and primary patient samples.