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Targeting the mitotic kinase NEK2 improves the efficacy of CDK4/6 inhibitors

ABSTRACT: Targeting the mitotic kinase NEK2 improves the efficacy of CDK4/6 inhibitors

PROVIDER: PRJNA1160795 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30656651_1.fastq.gz	Fastqsanger.gz
	SRR30656651_2.fastq.gz	Fastqsanger.gz
	SRR30656652_1.fastq.gz	Fastqsanger.gz
	SRR30656652_2.fastq.gz	Fastqsanger.gz
	SRR30656653_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Targeting the mitotic kinase NEK2 improves the efficacy of CDK4/6 inhibitors

Project description:Selective inhibitors that target cyclin dependent kinases 4 and 6 (CDK4/6i) are FDA approved for treatment of a subset of breast cancers and are being evaluated in numerous clinical trials for other cancers. Despite this advance, a subset of tumors are intrinsically resistant to these drugs and acquired resistance is nearly inevitable. Recent mechanistic evidence suggests that in addition to stalling the cell cycle, the anti-tumor effects of CDK4/6i involve the induction of chromosomal instability (CIN). Here, we exploit this mechanism by combining CDK4/6i with other instability-promoting agents to induce maladaptive CIN and irreversible cell fates. Specifically, dual targeting of CDK4/6 and the mitotic kinase NEK2 in vitro drives the accumulation of CIN that induces catastrophic mitoses, cell cycle exit, and cell death. Dual targeting also induces CIN in vivo and significantly decreases mouse tumor volume to a greater extent than either drug alone, without inducing toxicity. Importantly, we provide evidence that breast cancer cells are selectively dependent on NEK2, but non-transformed cells are not, in contrast with other mitotic kinases that are commonly essential in all cell types. These findings implicate NEK2 as a potential therapeutic target for breast cancer that could circumvent the dose-limiting toxicities that are commonly observed when blocking other mitotic kinases. Moreover, these data suggest that NEK2 inhibitors could be used to sensitize tumors to FDA-approved CDK4/6i for the treatment of breast cancers, improving their efficacy and providing a foundation for expanding the patient population that could benefit from CDK4/6i.

2025-03-05 | GSE277102 | GEO

Phosphoproteomics analysis of TAMs with NEK2 overexpression

Project description:NEK2 is considered a key factor in the maintenance of development and function of B cells in multiple myeloma (MM). Importantly, we previously demonstrated that PD-L1 is a substrate of NEK2, and combinatorial inhibition of NEK2 and PD-L1 largely improves the therapeutic efficacy of pancreatic cancer in pre-clinical models. But the expression and function of NEK2 in HCC-related TAMs have not yet been studied. This analysis revealed changes in the proteome due to the overexpression of NEK2 in TAMs, providing a valuable reference for further functional investigations.

2025-05-26 | PXD054708 | Pride

NEK2 regulates triple negative breast cancer transcriptome.

Project description:NEK2 is a mitotic kinase that is upregulated and mislocalized in the nucleus of human cancer cells. NEK2 modulates expression and activity of both transcription and splicing factors in cancer cells, nevertheless whether this kinase affects transcriptome regulation genome widely and whether this activity concurs to its oncogenic activity is still unknown. Herein, by high-throughput RNA sequencing analysis of MDA-MB-231 cells transiently silenced for NEK2 we uncover an extensive modulation of triple-negative breast cancer cell transcriptome by this kinase.

2021-12-21 | GSE140803 | GEO

Inhibition of CK1e potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer

Project description:In this study, we found that combination treatment of breast cells with CK1 inihbitor (D 4476) and CDK4/6 inhibitor (Ribociclib) exhibited greatly enhanced therapeutic efficacy than CDK4/6 inhiitor single treatment

2021-08-10 | GSE177054 | GEO

Effect of NEK2 deficiency on gene expression of CD19-selected spleen B cells of Eμ-myc mouse model

Project description:NEK2 overexpression in the B cell lineage affects B cell development. To determine whether deficiency of NEK2 inhibits B cell malignancies, we crossed Nek2 knockout mice with Eμ-myc transgenic mice, a well-established Myc-driven preclinical model for B cell malignancies. Three genotyping offsprings were obtained: Eμ-myc/Nek2+/+ (NEK2 wild type), Eμ-myc/Nek2+/- (NEK2 heterozygotes), and Eμ-myc/Nek2-/- (NEK2 homozygotes). Bulk RNA-seq was performed on CD19-selected spleen B cells to view the transcriptome differences.

2023-06-01 | GSE226675 | GEO

Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer

Project description:We report that NEK2 protein level is overexpressed and correlated with the tumor stage and lymph node metastasis in cervical cancer. Furthermore, we provided evidence that NEK2-depleted cervical cancer cells exhibit impaired oncogenesis and enhanced radiosensitivity. Using RNA sequencing, we identify Wnt1 as a key downstream effector of NEK2. Knockdown of NEK2 downregulates the mRNA and protein levels of Wnt1, thereby inhibiting the activation of the Wnt/β-catenin signaling pathway. More importantly, the observed consequences induced by NEK2 depletion in cervical cancer cells can be partially rescued by Wnt1 overexpression. Taken together, these results demonstrate that NEK2 activates the Wnt/β-catenin signaling pathway via Wnt1 to drive oncogenesis and radioresistance in cervical cancer, indicating that NEK2 may be a promising target for the radiosensitization of cervical cancer.

2021-04-30 | GSE148531 | GEO

LC-MS proteomics quantitative analysis of pancreatic cancer cells overexpressing NEK2

Project description:The NEK2 overexpression in pancreactic cancer cell (SW1990), and we performed LC-MS to further investigate the manner in which NEK2 regulates PD-L1.

2021-06-29 | PXD026877 | Pride

In Vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in Human Chordoma Xenografts [RNA-seq]

Project description:We evaluated the tumor efficacy of the CDK4/6 inhibitor palbociclib in two chordoma Patient’s Derived Xenograft (PDX) models to validate and identify novel therapeutic approaches.

2022-10-29 | GSE216418 | GEO

Gene expression profile at single cell level of bone marrow cells in 5TGM1 multiple myeloma mouse model of NEK2 deficiency

Project description:To determine how the lack of NEK2 in the tumor microenvironmental cells contributes to tumor inhibition and immune regulation, we used single cell RNA sequencing (scRNA-seq) to analyze the diversity of immune cells in the bone marrow of 5TGM1 MM mouse model with and without NEK2 deficiency.

2023-06-01 | GSE226697 | GEO

CDK4/6 inhibition promotes anti-tumor immunity

Project description:Pharmacologicalinhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approvedtreatment forhormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancertypes. The clinical success of these inhibitorsis largely attributedto well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is lessunderstood. Usingintegrated epigenomic, transcriptomic and proteomicanalyses, we demonstrateda novel action of CDK4/6inhibitorsin promoting the phenotypic and functional acquisition of immunological T cell memory.Short-term priming with a CDK4/6inhibitorpromoted long-termendogenousanti-tumor T cell immunityin mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive offavorable responses to immune checkpoint blockade in melanoma patients.Together, thesemechanistic insights significantlybroaden the prospective utility of CDK4/6 inhibitors as clinical tools to boostanti-tumorT cell immunity.

2021-06-08 | PXD026539 | Pride

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