ArticleThe FEBS journal2025
The AXL inhibitor bemcentinib overcomes microenvironment-mediated resistance to pioglitazone in acute myeloid leukemia.
Article in The FEBS journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Single-Cell RNA-Sequencing Reveals Tumor Microenvironment Composition and Prior Therapy Modulate Response to Axl Inhibition.Cellular and molecular bioengineering · 2026Article
- Genome Agnostic Reprogramming of Acute Myelocytic Leukemia Hallmarks by Targeting Non-Oncogene Addictions with Azacitidine Plus Pioglitazone and All-Trans Retinoic Acid.International journal of molecular sciences · 2026Review
- Assay development and screening of inhibitors targeting the SARS-CoV-2 2'-O-methyltransferase NSP16.Pharmaceutical science advances · 2025Article
- Disease-specific epigenetic deregulation of enhancers, transposons, and polycomb targets in acute promyelocytic leukemia.Genome medicine · 2025Article
- Review
- Article
- RNAi Screen Identifies AXL Inhibition Combined with Cannabinoid WIN55212-2 as a Potential Strategy for Cancer Treatment.Pharmaceuticals (Basel, Switzerland) · 2024Article
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
Prognosis of acute myeloid leukemia (AML) remains poor especially in older patients who are ineligible for standard chemotherapy or have refractory disease. Here, we study the potential of Peroxisome Proliferator-Activated Receptor (PPAR)-γ agonist pioglitazone to improve the treatment of AML. We show that pioglitazone exerts an anti-proliferative and anti-clonogenic effect on AML cell lines KG-1a, MOLM-14 and OCI-AML3 and on primary cultures from AML patients. However, co-culture of AML cells with stromal cells mimicking the bone marrow microenvironment counteracts this effect, suggesting the existence of a stroma-mediated resistance mechanism to pioglitazone. We show that pioglitazone treatment upregulates the receptor AXL in AML cells at the mRNA and protein level, allowing AXL to be phosphorylated by its ligand Gas6, which is secreted by the stroma. Addition of exogenous Gas6 or stromal cell conditioned medium also abolishes the anti-proliferative effect of pioglitazone, with an increase in AXL phosphorylation observed in both conditions. Co-incubation with the AXL inhibitor bemcentinib restored the anti-leukemic activity of pioglitazone in the presence of stromal cells by reducing AXL phosphorylation to its baseline level. We also confirm that this resistance mechanism is PPAR-γ-dependent as stromal cells invalidated for PPAR-γ are unable to inhibit the antileukemic effect of pioglitazone. Altogether, we suggest that pioglitazone treatment exerts an anti-leukemic effect but concomitantly triggers a stroma-mediated resistance mechanism involving the Gas6/AXL axis. We demonstrate that a combination of pioglitazone with an AXL inhibitor overcomes this mechanism in primary cultures and AML cell lines and exerts potent anti-leukemic activity requiring further evaluation in vivo through murine xenograft pre-clinical models.
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