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

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.