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Updated: Jan 7, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
Published on: June 6, 2025
CDK4/6 inhibition overcomes venetoclax resistance mechanisms with enhanced combination activity in acute myeloid
Melissa L Stewart1, Jessica Gibbs2, Kevin Watanabe-Smith1
1Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Abstract:
Venetoclax (ven) combined with azacytadine is a widely used therapy for acute myeloid leukemia (AML). However, most patients develop resistance. To identify more effective combinations, we analyze 302 AML patient samples and find ven plus palbociclib (ven+palbo), a cyclin dependent kinase (CDK)4/6 inhibitor, to be highly effective. Ven+palbo shows synergistic activity in AML cell lines and patient-derived xenograft mouse models. Patient samples exhibiting a synergistic response to ven+palbo show downregulation of genes involved in protein synthesis. Genome-wide (CRISPR) screening shows that loss of translational genes uniquely confers sensitivity to ven but not to ven+palbo. AML cells exposed to ven exhibit an adaptive increase of protein synthesis that is overcome by ven+palbo through regulation of translational machinery. Additionally, ven+palbo mitigates resistance mechanisms observed with single-agent ven (BAX loss) and palbo (RB1 loss). Finally, we identify the loss of IKZF1 as a mechanism of resistance to ven+palbo and show that targeting AXL is effective in IKZF1-mutated AML.
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