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

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE279981 | GEO | 2025/12/31

REPOSITORIES: GEO

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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

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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

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

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

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

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

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

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

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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.

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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.

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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.

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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

Protein arginine methyltransferase 5 (PRMT5) is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer [RNA-seq_siPRMT5]

Project description:CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout (RBKO) breast cancer cells. Inhibition of PRMT5 blocked the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), which led to Ser2 Pol II hyperphosphorylation, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibited growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight the potential of dual ER and PRMT5 blockade as a novel therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.

2023-07-11 | GSE236499 | GEO

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