Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML

The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, regardless of their genetic and non-genetic complexity. In this report, we leverage the vulnerability of AML cells to CDK6 to identify a combination therapy capable of targeting common biological processes shared by all leukemic cells, while sparing non-transformed cells. We demonstrate that the combined inhibition of CDK6 and LSD1 restores myeloid differentiation and depletes the leukemic progenitor compartment in AML samples. Mechanistically, this combination induces major changes in chromatin accessibility, leading to the transcription of differentiation genes and diminished LSC signatures. Remarkably, the combination is synergistic, induces durable changes in the cells, and is effective in PDX mouse models. While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2025-08-29
DOI
https://doi.org/10.1038/s44321-025-00296-2
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML

Paulo De Sepulveda, Nadine Carbuccia, Paraskevi Kousteridou, Rémy Castellano et al.
EMBO Molecular Medicine
Acute Myeloid Leukemia Research
article

Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML

Paulo De Sepulveda, Nadine Carbuccia, Paraskevi Kousteridou, Rémy Castellano, Julien Vernerey, Sébastien Letard, Armelle Goubard, Patrice Dubreuil, Yves Collette, Antonia Boudet, Lise M. Brault, Isabelle Vigon, Edwige Voisset, Jean‐Max Pasquet, Mathieu Desaunay, Sophie Lopez
article en

Abstract

The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, regardless of their genetic and non-genetic complexity. In this report, we leverage the vulnerability of AML cells to CDK6 to identify a combination therapy capable of targeting common biological processes shared by all leukemic cells, while sparing non-transformed cells. We demonstrate that the combined inhibition of CDK6 and LSD1 restores myeloid differentiation and depletes the leukemic progenitor compartment in AML samples. Mechanistically, this combination induces major changes in chromatin accessibility, leading to the transcription of differentiation genes and diminished LSC signatures. Remarkably, the combination is synergistic, induces durable changes in the cells, and is effective in PDX mouse models. While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.

EMBO Molecular MedicineVol. 17(10)
Centre National de la Recherche Scientifique (FR), Université de Bordeaux (FR), Inserm (FR), BioClinica (United States) (US), Acute Leukemia French Association (FR), Bordeaux Population Health (FR), Laboratoire de Neurosciences Intégratives et Adaptatives (FR), Centre de Recherche en Cancérologie de Marseille (FR), Institut Carnot ARTS (FR), BoRdeaux Institute of onCology (FR)
Fondation ARC pour la Recherche sur le Cancer, Fondation de France, Canceropôle PACA, Institut National Du Cancer, Groupement des Entreprises Françaises dans la lutte contre le Cancer, Société Française d'Hématologie, HORIZON EUROPE Marie Sklodowska-Curie Actions
Openalex Percentile: Top 71%
Acute Myeloid Leukemia Research
DOIOpen Access PDFOpenAlex
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