The synergistic tumor suppressor effect of CDK4/6 inhibitors and BRD4 inhibitors in acute myeloid leukemia.

[OBJECTIVE] The objective of this research is to explore the anti-leukemic properties of CDK4/6 inhibitors when used alongside BET inhibitors for treating acute myeloid leukemia (AML), as well as to clarify the molecular mechanisms involved.

[METHODS] Cell viability was assessed using the CCK-8 assay following treatment of AML cells with varying doses of SHR6390, a CDK4/6 inhibitor, and OTX015, a BET inhibitor.The time- and dose-dependent inhibitory effects of these two drugs on AML cells were assessed, and the respective IC50 and combination index (CI) values after co-treatment were calculated. The effects of SHR6390 and OTX015 on the growth potential of AML cells were additionally examined through soft agar colony formation assays and flow cytometry. Furthermore, RNA sequencing and Western blot analysis were conducted on cells treated with both drugs. The aim of this study is to explore the mechanism by which SHR6390 and OTX015 synergistically inhibit the proliferation of AML cells.The anti-tumor activity of SHR6390 and/or OTX015 in AML xenograft mice was also investigated through animal experiments.

[RESULTS] 1. Either the CDK4/6 inhibitor SHR6390 or the BRD4 inhibitor OTX015, or a combination of the two, were employed to hinder both the survival and proliferation of cell lines associated with acute myeloid leukemia, showing a synergistic effect. 2. The combined application of SHR6390 and OTX015 markedly suppresses the invasive and migratory capacities of acute myeloid leukemia cells.3. The use of both SHR6390 and OTX015 induces apoptosis in acute myeloid leukemia cells while also disrupting cell cycle progression, leading to a halt before DNA replication occurs. 4. SHR6390 and OTX015 hinder the proliferation of acute myeloid leukemia cells by targeting both the PI3K-AKT-mTOR and the Wnt-β-Catenin pathway. 5. SHR6390 and OTX015 Synergistically Inhibit the Growth of AML Xenografts In Vivo.