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Martinostat as a Novel HDAC Inhibitor to Overcome Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia

ABSTRACT: Martinostat as a Novel HDAC Inhibitor to Overcome Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia

PROVIDER: PRJNA1236844 | ENA |

REPOSITORIES: ENA

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Martinostat as a Novel HDAC Inhibitor to Overcome Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia

Project description: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. 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, thereby contributing to its anticancer activity. These findings highlight the potential of martinostat as a selective, low-toxicity HDACi that, when combined with TKIs, could provide an effective strategy to overcome drug resistance in CML and improve therapeutic outcomes.

2025-07-23 | GSE292088 | GEO

Tyrosine Kinase Inhibitor Cardiotoxicity

Project description:Tyrosine Kinase Inhibitor Cardiotoxicity

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High-Throughput Screening of Human Induced Pluripotent Stem Cell Cardiomyocytes Predicts Tyrosine Kinase Inhibitor Cardiotoxicity

Project description:High-Throughput Screening of Human Induced Pluripotent Stem Cell Cardiomyocytes Predicts Tyrosine Kinase Inhibitor Cardiotoxicity

2016-10-20 | GSE88944 | GEO

Optimized Response Assessment of Gastrointestinal Stromal Tumors Using Dual-Energy CT: A Prospective Multicenter-Multinational Trail in Patients Undergoing Targeted Therapy with a tyrosine-kinase-inhibitor

Project description:Interventions: Group 1: Patients with Gastrointestinal Stromal Tumors undergoing tyrosine kinase inhibitor treatment will be assessed regarding progression-free survival and overall survival within 2 years using the standard response criteria, in particular Response Evaluation Criteria In Solid Tumors, the WHO criteria for response, the tumor lesion volume as well as tumor density (according to Choi). Group 2: Patients with Gastrointestinal Stromal Tumors undergoing tyrosine kinase inhibitor treatment will be assessed regarding progression-free survival and overall survival within 2 years using the response criteria, in particular tumor lesion iodine uptake. Primary outcome(s): Progression-free survival within 2 years. Study Design: Allocation: Non-randomized controlled study; Masking: Open (masking not used); Control: active; Assignment: parallel; Study design purpose: treatment

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Fenebrutinib, a Bruton’s tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways

Project description:Fenebrutinib, a Bruton’s tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways

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Proteomic profiling by array of tyrosine kinase activity in metastatic malignant melanoma from human tissue specimens

Project description:Tyrosine kinase activity profiling of metatstatic malignant melanoma and normal skin tissue samples was performed using peptide kinase arrays. All samples were run in triplicates with and withouth inhbitor PLX4032 and Sutent Malate in order to identify how tyrosine kinases responds to kinase inhibitor treatment, ex vivo.

2013-01-17 | E-MTAB-1245 | biostudies-arrayexpress

A bruton’s tyrosine kinase inhibitor reduces stemness and invasiveness of patient-derived glioblastoma tumorspheres

Project description:A bruton’s tyrosine kinase inhibitor reduces stemness and invasiveness of patient-derived glioblastoma tumorspheres

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Multiscale profiling of tyrosine kinase inhibitor cardiotoxicity reveals mechanosensitive ion channel PIEZO1 as cardioprotective

Project description:Multiscale profiling of tyrosine kinase inhibitor cardiotoxicity reveals mechanosensitive ion channel PIEZO1 as cardioprotective

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The tyrosine kinase inhibitor GNF-7 targets senescent cells through allosteric activation of GCN2

Project description:The tyrosine kinase inhibitor GNF-7 targets senescent cells through allosteric activation of GCN2

| PRJNA1288031 | ENA

The tyrosine kinase inhibitor GNF-7 targets senescent cells through allosteric activation of GCN2

Project description:The one-two-punch approach refers to the sequential administration of two different chemotherapies, the second of which targets cancer cells that resisted the initial treatment. To find such a second punch, we performed a chemical screen to find drugs that are preferentially toxic for cells with an activated DNA damage response (DDR). This screen identified the tyrosine kinase inhibitor GNF-7 as a top hit. Subsequent work revealed that GNF-7 is a potent senolytic, even when senescence is triggered by therapies that do not activate the DDR. Consistently, GNF7 is highly efficacious to kill cancer cells previously treated with CDK4/6 inhibitors, including in patient-derived organoids and mouse xenografts. Surprisingly, the senolytic effect of GNF-7 is not mediated by the inhibition of a tyrosine kinase (TK), but rather by the allosteric activation of GCN2, an effect previously reported for other TK inhibitors. Together, our study reports the discovery of a novel senolytic agent that strongly synergizes with CDK4/6 inhibitors when applied sequentially and expands our understanding of the mechanisms behind the anticancer effects of TK inhibitors.

2025-09-01 | GSE301995 | GEO

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