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Low Molecular Weight Cyclin E Confers a Vulnerability to PKMYT1 Inhibition in Triple-Negative Breast Cancer

ABSTRACT: Low Molecular Weight Cyclin E Confers a Vulnerability to PKMYT1 Inhibition in Triple-Negative Breast Cancer

PROVIDER: PRJNA1144132 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30126533_1.fastq.gz	Fastqsanger.gz
	SRR30126533_2.fastq.gz	Fastqsanger.gz
	SRR30126534_1.fastq.gz	Fastqsanger.gz
	SRR30126534_2.fastq.gz	Fastqsanger.gz
	SRR30126535_1.fastq.gz	Fastqsanger.gz

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Low Molecular Weight Cyclin E Confers a Vulnerability to PKMYT1 Inhibition in Triple-Negative Breast Cancer

Project description:Cyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. Cleavage of full-length cyclin E (FL-cycE) to low molecular weight isoforms (LMW-E) dramatically alters the substrate specificity, promoting G1/S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1 also plays an important role in mitosis by inhibiting CDK1 to block premature mitotic entry, suggesting it could be a therapeutic target in TNBC expressing LMW-E. Here, analysis of TNBC patient tumor samples revealed that co-expression of LMW-E and PKMYT1-catalyzed CDK1 phosphorylation predicted poor response to neoadjuvant chemotherapy. Compared to FL-cycE, LMW-E specifically upregulated PKMYT1 expression and protein stability, elevating CDK1 phosphorylation. Inhibiting PKMYT1 with the selective inhibitor RP-6306 (lunresertib) elicited LMW-E dependent antitumor effects, accelerating premature mitotic entry, inhibiting replication fork restart, and enhancing DNA damage, chromosomal breaks, apoptosis, and replication stress. Importantly, TNBC cell line xenografts expressing LMW-E showed greater sensitivity to RP-6306 than tumors with empty vector or FL-cycE. Furthermore, RP-6306 exerted tumor suppressive effects in LMW-E transgenic murine mammary tumors and LMW-E-high TNBC patient-derived xenografts but not in the LMW-E null models examined in parallel. Lastly, transcriptomic and immune profiling demonstrated that RP-6306 treatment induced interferon responses and T-cell infiltration in the LMW-E-high tumor microenvironment, enhancing the antitumor immune response. These findings highlight the LMW-E/PKMYT1/CDK1 regulatory axis as a promising therapeutic target in TNBC, providing the rationale for further clinical development of PKMYT1 inhibitors in this aggressive breast cancer subtype.

2024-08-09 | GSE273940 | GEO

Targeting EZH2 increases the vulnerability of triple-negative breast cancer

Project description:Targeting EZH2 increases the vulnerability of triple-negative breast cancer

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MYC-Alarmin Axis as a Novel Therapeutic Vulnerability in Triple Negative Myeloproliferative Neoplasms

Project description:Despite advances in our understanding of the underlying genetic abnormalities in myelofibrosis (MF) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly in triple negative MF patients who lack mutations in the JAK2 kinase pathway. Here we report that MYC copy number gain (e.g., trisomy 8) is frequently identified in triple negative MF where MF development and progression rely on MYC-directed activation of S100A9, a Danger Associated Molecular Pattern (DAMP) protein that plays pivotal roles in inflammation. Notably, MYC-S100A9 axis underlies complex network of inflammatory signaling that involves various hematopoietic cell types in the bone marrow microenvironment. Accordingly, small molecules targeting the MYC-S100A9 pathway effectively ameliorated the MF phenotypes, highlighting MYC-alarmin axis as a novel therapeutic vulnerability in a subgroup of MF patients.

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Differential gene expression in adipose tissue from obese human subjects during weight loss and weight maintenance

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MYC-Alarmin Axis as a Novel Therapeutic Vulnerability in Triple Negative Myeloproliferative Neoplasms

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Cortical region confers neuron-type-specific vulnerability to human APP expression

Project description:Alzheimer’s Disease is a devastating and an irreversible neurodegenerative disease currently afflicting 50 million individuals worldwide, a number expected to escalate three-fold over the next 25 years. Preventative treatment is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer’s Disease remain unknown. In human patients with Alzheimer’s Disease, the earliest observed pathophysiological correlate to cognitive decline is hyperexcitability. In mouse models, early hyperexcitability has been shown in the cortical region first impacted by Alzheimer’s Disease. The origin of hyperexcitability in early stage-disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type- specific proteomics and patch-clamp electrophysiology, we uncovered differential susceptibility to human-specific APP in a model of sporadic Alzheimer’s Disease. Shockingly, our findings reveal that early entorhinal hyperexcitability may result from intrinsic vulnerability of parvalbumin interneurons, prior to changes in surrounding excitatory neurons. This study suggests early disease interventions addressing non-excitatory cell-types may protect regions first vulnerable to pathological symptoms of Alzheimer’s Disease and downstream cognitive decline.

2024-06-28 | PXD053491 | Pride

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