Clinical epigenetics · 2025
Martinostat as a novel HDAC inhibitor to overcome tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
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Yang Haeun, Li Vladimir, Park Su Jung, Cheon Sang Won, Lorant Anne, Mazumder Aloran, Lee Jin Young, Orlikova-Boyer Barbora, Cerella Claudia, Christov Christo, Kirsch Gilbert, Olberg Dag Erlend, Bormans Guy, Kang Hyoung Jin, Han Byung Woo, Schnekenburger Michael, Diederich Marc
Аннотация
BACKGROUND: Chronic myeloid leukemia (CML) remains a therapeutic challenge, particularly in patients who develop resistance to standard tyrosine kinase inhibitors (TKIs) such as imatinib. Here, we present the first demonstration of the potent anti-leukemic activity of the histone deacetylase (HDAC) inhibitor martinostat in both TKI-sensitive and TKI-resistant CML.
METHODS AND RESULTS: Structural and biochemical analyses confirmed the efficient and selective binding of martinostat to HDAC isoenzyme ligand-binding pockets, resulting in histone and tubulin hyperacetylation in both imatinib-sensitive and resistant CML cells, outperforming vorinostat, a clinically used HDAC inhibitor (HDACi). It selectively impaired CML cell proliferation and viability and induced apoptosis across various CML models, including resistant cell models and patient blasts, with minimal toxicity to healthy cells and low developmental toxicity in zebrafish. In addition to its single-agent efficacy, martinostat demonstrated enhanced anticancer effects when combined with imatinib, both in vitro and in vivo, significantly reducing tumor growth in resistant CML xenograft models. Mechanistically, mRNA-seq data showed that martinostat disrupted key survival signaling pathways and amplified apoptotic responses, contributing to its anticancer activity.
CONCLUSIONS: These findings highlight the potential of martinostat as a selective, low-toxicity HDACi that, combined with TKIs, could provide an effective strategy to overcome drug resistance in CML and improve therapeutic outcomes.
METHODS AND RESULTS: Structural and biochemical analyses confirmed the efficient and selective binding of martinostat to HDAC isoenzyme ligand-binding pockets, resulting in histone and tubulin hyperacetylation in both imatinib-sensitive and resistant CML cells, outperforming vorinostat, a clinically used HDAC inhibitor (HDACi). It selectively impaired CML cell proliferation and viability and induced apoptosis across various CML models, including resistant cell models and patient blasts, with minimal toxicity to healthy cells and low developmental toxicity in zebrafish. In addition to its single-agent efficacy, martinostat demonstrated enhanced anticancer effects when combined with imatinib, both in vitro and in vivo, significantly reducing tumor growth in resistant CML xenograft models. Mechanistically, mRNA-seq data showed that martinostat disrupted key survival signaling pathways and amplified apoptotic responses, contributing to its anticancer activity.
CONCLUSIONS: These findings highlight the potential of martinostat as a selective, low-toxicity HDACi that, combined with TKIs, could provide an effective strategy to overcome drug resistance in CML and improve therapeutic outcomes.