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Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [BrU-Seq]

ABSTRACT: Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [BrU-Seq]

PROVIDER: PRJNA977985 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24774301_1.fastq.gz	Fastqsanger.gz
	SRR24774301_2.fastq.gz	Fastqsanger.gz
	SRR24774302_1.fastq.gz	Fastqsanger.gz
	SRR24774302_2.fastq.gz	Fastqsanger.gz
	SRR24774303_1.fastq.gz	Fastqsanger.gz

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Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [RNA-Seq]

Project description:KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and regulate diverse biological processes including transcription, cell-cycle progression, and stem cell development. KAT6A exerts an oncogenic role in several tumor types including breast cancer where it is amplified in 10-15% of patients. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a novel benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.

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Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [ATAC-Seq]

2023-06-05 | GSE233784 | GEO

Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [BrU-Seq]

2023-06-05 | GSE233787 | GEO

Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [ChIP-Seq - CUT&RUN]

2023-06-05 | GSE233788 | GEO

Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363

Project description:Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363

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Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [RNA-Seq]

Project description:Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [RNA-Seq]

| PRJNA977982 | ENA

Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [ATAC-Seq]

Project description:Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [ATAC-Seq]

| PRJNA977984 | ENA

Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [ChIP-Seq - CUT&RUN]

Project description:Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363 [ChIP-Seq - CUT&RUN]

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Targeting KAT6A/KAT6B dependencies in breast cancer with a novel selective, orally bioavailable KAT6 inhibitor, CTx-648/PF-9363

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-06-05 | GSE233789 | GEO

Catalytic inhibition of KAT6 /KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia [RNA-seq]

Project description:Understanding the molecular pathogenesis of MLL leukaemia has led to the development of epigenetic therapies that have altered the natural history of this often-incurable disease. Here, using complementary genetic and pharmacological approaches, we define the individual and combined contribution of the MYST acetyltransferases, KAT6A, KAT6B and KAT7, to MLL fusion oncoprotein (MLL-FP) driven acute leukaemia. We show that inhibition of KAT6A/B is efficacious in some but not all MLL-FP pre-clinical models; however, simultaneous targeting of KAT7 increases the therapeutic effect. At a molecular level, KAT7 interacts with Menin and other members the MLL complex and we demonstrate that these epigenetic regulators are co-localised at chromatin where they co-regulate the oncogenic transcriptional program initiated and maintained by the MLL-FP. Catalytic inhibition of KAT6/KAT7 with the novel small molecule inhibitor PF-9363 provides an orthogonal route to Menin inhibition to disable the transcriptional activity of MLL-FP. This is of clinical importance as PF-9363 or genetic depletion of KAT7 is able to overcome both genetic and non-genetic acquired resistance to Menin inhibition. Moreover, combined inhibition of KAT6/KAT7 and Menin results in a rapid eviction of chromatin bound MLL-FP and a profound repression of the oncogenic transcriptional program resulting in marked synergistic benefit in pre-clinical models of primary resistance to single agent therapy. Together these data provide the molecular rationale for rapid clinical translation of combination therapy to further improve clinical outcomes in MLL-FP leukaemia.

2025-06-17 | GSE277100 | GEO

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