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
  • 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.
Products