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CDK4/6i enhances the antitumor effect of PD1 antibody by promoting TLS formation in ovarian cancer

ABSTRACT: CDK4/6i enhances the antitumor effect of PD1 antibody by promoting TLS formation in ovarian cancer

PROVIDER: PRJNA980122 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24833980_1.fastq.gz	Fastqsanger.gz
	SRR24833980_2.fastq.gz	Fastqsanger.gz
	SRR24833981_1.fastq.gz	Fastqsanger.gz
	SRR24833981_2.fastq.gz	Fastqsanger.gz
	SRR24833982_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

CDK4/6i enhances the antitumor effect of PD1 antibody by promoting TLS formation in ovarian cancer

Project description:Ovarian cancer is insensitive to immunotherapy and has a high mortality rate. CDK4/6 inhibitors (CDK4/6i) regulate the tumor microenvironment and play an antitumor role. Our previous research demonstrated that lymphocyte aggregation (tertiary lymphoid structures, TLS) was observed after CDK4/6i treatment. This may explain the synergistic action of CDK4/6i with the anti-PD1 antibody. However, the key mechanism by which CDK4/6i promotes TLS formation has not been elucidated. We examine the link between TLS and prognosis. Animal models and high-throughput sequencing were used to explore the potential mechanism by which CDK4/6i promotes TLS formation. Our results showed the presence of TLSs was associated with a favorable prognosis for ovarian cancer. CDK4/6i promoted TLS formation and enhanced the immunotherapeutic effect of the anti-PD1 antibody. The potential mechanism of CDK4/6i affecting the formation of TLS may be through modulating SCD1 and its regulatory molecules ATF3 and CCL4. Our findings provide a theoretical basis for the application of CDK4/6i in ovarian cancer.

2023-10-12 | GSE234106 | GEO

CDK4/6i enhances the antitumor effect of PD1 antibody by promoting TLS formation in ovarian cancer.

Project description:Ovarian cancer is insensitive to immunotherapy and has a high mortality rate. CDK4/6 inhibitors (CDK4/6i) regulate the tumor microenvironment and play an antitumor role. Our previous research demonstrated that lymphocyte aggregation (tertiary lymphoid structures, TLSs) was observed after CDK4/6i treatment. This may explain the synergistic action of CDK4/6i with the anti-PD1 antibody. However, the key mechanism by which CDK4/6i promotes TLS formation has not been elucidated. We examine the link between TLS and prognosis. Animal models and high-throughput sequencing were used to explore the potential mechanism by which CDK4/6i promotes TLS formation. Our results showed the presence of TLSs was associated with a favorable prognosis for ovarian cancer. CDK4/6i promoted TLS formation and enhanced the immunotherapeutic effect of the anti-PD1 antibody. The potential mechanism of CDK4/6i affecting the formation of TLS may be through modulating SCD1 and its regulatory molecules ATF3 and CCL4. Our findings provide a theoretical basis for the application of CDK4/6i in ovarian cancer.

| S-EPMC10559077 | biostudies-literature

A genome-wide CRISPRa screening to functionalize lncRNAs in CDK4/6i response [activation_RNAseq]

Project description:RNA-seq data for candidate genes identified from CRISPR activation screen for regulation of CDK4/6i response

2025-12-31 | GSE254283 | GEO

A genome-wide CRISPRa screening to functionalize lncRNAs in CDK4/6i response [siRNA_RNAseq]

Project description:RNA-seq data for candidate genes identified from CRISPR activation screen for regulation of CDK4/6i response

2025-12-31 | GSE279981 | GEO

Downregulation of NSRP1 confers CDK4/6i resistance in breast cancer via activation of the IFN signaling pathway

Project description:Via analyzing the expression matrix of palbociclib-sensitive and palbociclib-resistant tumors from patients with breast cancer, it was revealed that NSRP1 is associated with CDK4/6i resistance. Therefore, RNA Sequencing is performed for MCF7 cells transfected with ctr or NSRP1 siRNA to study the molecular mechanism of NSRP1 in mediating CDK4/6i resistance in breast cancer cells.

2025-01-29 | GSE270673 | GEO

RNA sequencing of luminal breast cancer patient-derived xenografts (PDX) library to capture tumor heterogeneity and explore the mechanisms of resistance to CDK4/6 inhibitors

Project description:Combining CDK4/6 inhibitors (CDK4/6i) with endocrine therapy has proven clinically effective and represents now the first-line treatment for advanced Luminal Breast Cancer (LBC) patients. However, resistance to CDK4/6i almost invariably arises in these patients, emphasising the critical need to comprehend these mechanisms and develop new strategies to overcome resistance. We report on the generation and characterisation of a LBC PDX displaying acquired resistance to CDK4/6i palbociclib. Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumour shrinkage, some tumours might eventually regrow under drug treatment. RNA sequencing, followed by gene set enrichment analyses, unveiled that this PDX have become refractory to CDK4/6i, both at biological and molecular level.

2024-11-18 | E-MTAB-14085 | biostudies-arrayexpress

ESR1 Y537S and D538G mutations drive resistance to CDK4/6 inhibitors in estrogen receptor-positive breast cancer

Project description:Purpose: Breast cancers with ESR1 mutations are resistant to antiestrogen therapy. We aimed to investigate the association of ESR1 mutations with resistance to CDK4/6 inhibitors (CDK4/6i) using real-world data analysis and experimental validation. Patients and Methods: A total of 3,958 patients with estrogen receptor-positive (ER+) metastatic breast cancer with DNA sequencing data were analyzed. Breast tumor DNA and circulating tumor (ct) DNA were sequenced using the Tempus xT tumor assay and Tempus xF liquid biopsy, respectively. Patients were stratified into either treated with CDK4/6i (breast tumors: 1,070; ctDNA: 1,885) or CDK4/6i naïve (breast tumors: 750; ctDNA: 253). Engineered MCF7 cells carrying ESR1 Y537S or D538G knock-in mutations were used to study antitumor efficacy of the CDK4/6i, palbociclib in vitro and in vivo. Results: In both xF and xT assays, ESR1 mutations were the only somatic alterations significantly more frequent in those who received CDK4/6i than those who did not. Knock-in of ESR1 Y537S or ESR1 D538G in MCF7 cells resulted in upregulation of cell cycle-related gene signatures upon treatment with CDK4/6i ± antiestrogen compared to cells with non-mutant ESR1. MCF7 xenografts harboring ESR1 Y537S and D538G mutations established in nude mice were resistant to palbociclib. Conclusions: We report herein real-world and preclinical evidence that ESR1 mutations, particularly Y537S and D538G, can drive resistance to CDK4/6 inhibitors.

2024-11-12 | GSE281302 | GEO

Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders

Project description:CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.

2022-02-16 | PXD023137 | Pride

A genome-wide CRISPRa screening to functionalize lncRNAs in CDK4/6i response

Project description:Aberrant cell cycle regulation is one of central hallmarks for cancer, and cyclin-dependent kinase inhibitors (CDKi) have showed promising clinical outcome in treating ER+/HER2- breast cancer patients. There are also increasing pre-clinical and clinical studies trying to expand the usage of CDKi to more cancer types. However, the underlying mechanism of high individual variability in clinical response remains unclear. LncRNAs are a group of long non-coding RNAs, which have emerged as regulators and biomarkers for cancer therapeutic outcome. In this study, we first performed a CRISPR activation screen of 9744 lncRNAs in breast cancer cells treated with Palbociclib. We identified 144 and 152 lncRNAs that lead to Palbociclib sensitivity and resistance (FDR<0.05), respectively. Further pharmacogenomic analysis from 41 breast cancer cell lines suggested 34 lncRNAs as potential regulators for Palbociclib response (p<0.05). Targeted screen of overlapped lncRNAs and positive control protein-coding genes was performed to further narrow down the hits. Interestingly, we observed a significant association between cancer cell proliferation and Palbociclib response from both screens. Experimental validation of the screen demonstrated that activation of lncRNA CSS1, CSS2 and CSS3 lead to Palbociclib sensitivity. Mechanically, RNA-seq analysis suggested that they may promote cell cycle progression and downregulate cancer stemness. Collectively, our study characterized novel lncRNAs involved in CDK4/6i response which can act as biomarkers for CDK4/6i treatment in cancer patients.

2025-12-31 | GSE253290 | GEO

TNBC response to CDK4/6 inhibitors plus RANKL inhibitors

Project description:CDK4/6i alone have proven to be largely ineffective in TNBC, even in the presence of functional retinoblastoma protein (pRB). In this study, we investigated the role of the RANK pathway in the response to CDK4/6i in pRB-proficient TNBC. Transcriptomic analysis of xenografts revealed that combining CDK4/6i with RANKLi more effectively arrested the cell cycle.

2025-05-20 | GSE277615 | GEO

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