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

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

PROVIDER: PRJNA736983 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14790291_1.fastq.gz	Fastqsanger.gz
	SRR14790291_2.fastq.gz	Fastqsanger.gz
	SRR14790292_1.fastq.gz	Fastqsanger.gz
	SRR14790292_2.fastq.gz	Fastqsanger.gz
	SRR14790293_1.fastq.gz	Fastqsanger.gz

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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

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

SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors

Project description:The CDK4/6 kinase is dysregulated in melanoma highlighting a potential therapeutic benefit. Indeed, such CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern and the molecular mechanisms of such resistance remain undefined. Here, we demonstrate that reactivation of mTORC1 signaling through increased expression of the amino acid transporter, SLC36A1, drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms; 1) Rb loss which drives SLC36A1 via reduced suppression of E2f; 2) FXR1 overexpression which promotes SLC36A1 translation and subsequently mTORC1. Finally, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo providing an important avenue for improved therapeutic intervention in aggressive melanoma.

2021-04-13 | GSE113268 | GEO

Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer.

Project description:Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes βTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors.

| S-EPMC8433397 | biostudies-literature

Therapeutic efficacy of INX-315, a selective CDK2 inhibitor, in solid tumors

Project description:Therapeutic efficacy of INX-315, a selective CDK2 inhibitor, in solid tumors

| PRJNA1016438 | ENA

In Vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in Human Chordoma Xenografts

Project description:In Vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in Human Chordoma Xenografts

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Gene expression alterations associated with acquired-resistance to the CDK4/6 inhibitor palbociclib [Palbociclib resistance_RNASeq]

Project description:RNA-seq was performed to compare the transcriptional programmes of palbociclib-resistant A375 and CHL1 cells compared to their parental counterparts Cyclin dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor positive breast cancer and are currently in clinical development in melanoma; a tumour that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib, and demonstrated that palbociclib-mediated inhibition of PRMT5 is essential for sensitivity to CDK4/6 inhibitors. Mechanistically, by inhibiting PRMT5 activity, palbociclib alters MDM4 pre-mRNA splicing leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 increases p21 leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treatment naïve and resistant models and also delays the emergence of resistance. Our studies have uncovered a novel mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide pre-clinical evidence that co-inhibition of CDK4/6 and PRMT5 is an effective and well tolerated therapeutic strategy. Overall our data provides a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors in not only melanoma but other tumour types including breast, pancreatic and esophageal carcinoma.

2019-08-23 | GSE133567 | GEO

RNA-Seq of rheumatoid arthritis synovial fibroblasts treated with CDK4/6 inhibitor and TNF+IL-1b stimulation

Project description:We prepared five RASF samples from each donor under four conditions: in the presence or absence of CDK4/6 inhibitor, palbociclib, and with or without cytokine stimulations. In total, 20 samples were analyzed. RASFs were treated with CDK4/6 inhibitor for 24 hours in advance to the stimulation. RNA was collected after 24 hours of the stimulation(TNF+IL-1b, 0.2ng/ml each)

2023-01-26 | E-MTAB-10795 | biostudies-arrayexpress

CDK4/6 inhibitor resistance in prostate cancer

Project description:CDK4/6 kinase inhibitors have shown great promise in clinical trials in various cancer types and have recently entered clinical trial for advanced prostate cancer. Although patients are expected to respond well to this class of drugs, development of resistance in some patients is anticipated. To pre-empt this and study how prostate cancer may evade CDK4/6 inhibition, new resistance models were generated from LNCaP and LAPC4 prostate cancer cells cells by prolonged culturing in presence of 0.5uM palbociclib. A shotgun phosphoproteomics approach was utilized and integrated with RNA sequencing data to unravel the molecular underpinnings of acquired resistance to palbociclib and resultant broad CDK4/6 inhibitor resistance.

2018-05-16 | PXD006561 | Pride

A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma

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