Synergistic potential of CDK4/6 inhibitors and ATRA in non‐APL AML

Summary Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by diverse genetic abnormalities. The standard of care remains to be chemotherapy and stem cell transplantation. In acute promyelocytic leukaemia (APL), differentiation therapy with all‐trans retinoic acid (ATRA) has significantly improved outcomes. Despite this, the success of ATRA has yet to be transferred to non‐APL AML. Exploring combinations to enhance the efficacy of ATRA in non‐APL AML remains a key focus. To investigate the therapeutic effect of ATRA in combination with cyclin‐dependent kinase 4/6 (CDK4/6) inhibitors in non‐APL AML. Non‐APL AML cell lines and primary patient samples were treated with ATRA and CDK4/6 inhibitors. Key outcomes included differentiation, proliferation, cell viability and colony‐forming capacity. Combination synergy was evaluated, and gene expression analysis identified pathways associated with therapeutic effects. The combination demonstrated dose‐dependent effects, enhancing differentiation and reducing proliferation, cell viability and colony‐forming capacity. A synergistic effect was observed across AML cell lines. Gene expression profiling revealed the co‐regulation of differentiation‐associated genes, unveiling the mechanisms driving therapeutic synergy. Combination of CDK4/6 inhibitors with ATRA shows potential for differentiation‐based AML treatment. This approach offers a promising avenue for improved outcomes in non‐APL AML.