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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

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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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Bruton’s tyrosine kinase inhibitor leads to bidirectional transcript regulation of Nurr1: A new key to Parkinson’s disease

Project description:Parkinson’s disease (PD) is a progressive neurological movement diseases with few therapeutic targets identified to date. The primary treatment for PD is levodopa, but it is only effective in the initial stage and induces side effects of the disease. To address this problem, we unveil the hitherto uncharacterized crucial role of Bruton’s tyrosine kinase protein (BTK) as a bidirectional transcriptional bio-regulator of tyrosine hydroxylase (TH) expression via the modulation of nuclear receptor-related transcription factor 1 (Nurr1). The proteomics competition binding assay revealed that BTK binds to Nurr1 and transactivates TH promoter activity via Nurr1. The BTK inhibitor demonstrated remarkable effects in the mitochondrial permeability transition pore-induced oxidative stress model by significantly attenuating the levels of proinflammatory mediators via WNT/β-catenin and MAPK kinase signaling. These findings highlight the potential efficacy of BTK inhibitors as innovative therapeutics for PD.

2024-10-21 | GSE279704 | GEO

SNP chip data of CML, resistant with tyrosine kinase inhibitor

Project description:To elucidate whether tyrosine kinase inhibitor (TKI) resistance in CML is associated with characteristic genomic alterations, we analyzed DNA samples from 45 TKI resistant CML patients with 250K single nucleotide polymorphism (SNP) arrays. From 20 patients, matched serial samples of pre-treatment and TKI resistance time points were available. 11 of the 45 TKI resistant patients had mutations of BCR-ABL1, including two T315I mutations. Besides known TKI resistance associated genomic lesions such as duplication of the BCR-ABL1 gene (n=8) and trisomy 8 (n=3), recurrent submicroscopic alterations including acquired uniparental disomy were detectable on chromosomes 1, 8, 9, 17, 19 and 22. On chromosome 22, newly acquired and recurrent deletions of the IGLC1 locus were detected in three patients, who had previously presented with lymphoid or myeloid blast crisis. This may support a hypothesis of TKI induced selection of subclones differentiating into immature B-cell progenitors as a mechanism of disease progression and evasion of TKI sensitivity. Keywords: SNP-chip

2010-02-09 | GSE18964 | GEO

Reduced Proteolytic Shedding of Receptor Tyrosine Kinases is a Post-Translational Mechanism of Kinase Inhibitor Resistance.

Project description:Expression data from MDA-MB231 human breast cancer cells treated with metalloproteinase inhibitor (10uM BB94), MEK inhibitor (3uM PD325901), or DMSO control shows substantial overlap in the transcriptional responses arising from MEK and protease inhibition, suggesting a shared mechanism of action. Kinase inhibitor resistance often involves upregulation of poorly understood “bypass” signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTKs) including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of melanoma patients treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured non-invasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance.

2016-03-21 | GSE77868 | GEO

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