2. Academic Validation
  3. CDK4/6 inhibition overcomes venetoclax resistance mechanisms with enhanced combination activity in acute myeloid leukemia

CDK4/6 inhibition overcomes venetoclax resistance mechanisms with enhanced combination activity in acute myeloid leukemia

  • Cell Rep Med. 2025 Dec 29:102526. doi: 10.1016/j.xcrm.2025.102526.
Melissa L Stewart 1,  Jessica Gibbs 2,  Kevin Watanabe-Smith 1,  Ariel Nguyen 2,  Isabel Kenna 2,  Karina Thiel-Klare 2,  Andy Kaempf 3,  Daniel Bottomly 4,  Stephen E Kurtz 1,  Christopher A Eide 2,  Nicola Long 2,  Jennifer N Saultz 2,  Luca Sax 2,  Ariane Huang 2,  Shannon K McWeeney 5,  Bill H Chang 6,  Jeffrey W Tyner 7
Affiliations

Affiliations

  • 1 Division 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.
  • 2 Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
  • 3 Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Biostatistics Shared Resource, Oregon Health & Science University, Portland, OR 97239, USA.
  • 4 Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
  • 5 Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR, USA; Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
  • 6 Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Division of Hematology and Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
  • 7 Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. Electronic address: [email protected].
PMID: 41468895 DOI: 10.1016/j.xcrm.2025.102526
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.

Keywords

cell state; monocytic; progenitor; targeted therapy.

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