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CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer

ABSTRACT: CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer

PROVIDER: PRJNA471762 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7174660.fastq.gz	Fastqsanger.gz
	SRR7174661.fastq.gz	Fastqsanger.gz
	SRR7174662.fastq.gz	Fastqsanger.gz
	SRR7174663.fastq.gz	Fastqsanger.gz
	SRR7174664.fastq.gz	Fastqsanger.gz

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CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer

Project description:The study evaluated the differential gene expression in CBX5 knockdown cells compared to control shRNA expressed HCC827 cells. Briefly, human lung cancer HCC827 cells stably expressing either CBX5 shRNAs or control shRNA were analysed for gene expression.

2023-01-05 | GSE114563 | GEO

CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer.

Project description:Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFRi) are approved for treating EGFR-mutant lung adenocarcinoma (LUAD), emergence of acquired resistance limits their clinical benefits. Several mechanisms for acquired resistance to EGFRi in LUAD have been identified; however, the molecular basis for this resistance remains unknown in ~30% of LUAD. Chromatin and DNA modifiers and their regulators play important roles in determining response to anticancer therapies. Therefore, to identify nongenetic mechanisms of EGFRi resistance in LUAD, we performed an epigenome-wide shRNA screen targeting 363 human epigenetic regulator genes. This screen identified loss of the transcriptional repressor chromobox homolog 5 (CBX5) as a driver of EGFRi resistance in EGFR-mutant LUAD. Loss of CBX5 confers resistance to multiple EGFRi in both cell culture and mice. We found that CBX5 loss in EGFR-mutant LUAD cells leads to increased expression of the transcription factor E2F1, which in turn stimulates expression of the antiapoptotic gene BIRC5 (survivin). This E2F1-mediated upregulation of BIRC5 in CBX5-knockdown LUAD cells attenuates apoptosis induction following EGFRi treatment. Consistent with these results, knockdown of E2F1 or BIRC5 partly rescues CBX5-knockdown-induced EGFRi resistance in cell culture and mice. EGFRi-resistant LUAD cell lines show reduced CBX5 expression compared to parental lines; however, bromo- and extra-terminal (BET)-domain inhibitors (BETi) restore CBX5 expression in these cells and sensitize them to EGFRi/BETi combination therapy. Similarly, treatment with a BIRC5 inhibitor suppresses growth of EGFRi-resistant LUAD cells. Collectively, these studies identify CBX5 loss as a driver of EGFRi resistance and reveal therapeutic opportunities for treating EGFRi-resistant LUAD.

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Splicing targeting approaches highlight actionable vulnerabilities in triple negative breast cancer

Project description:To investigate if pharmacological inhibition of splicing could uncover novel actionable vulnerabilities in TNBC, we profiled the genome-wide transcriptional changes elicited in MDA-MB-231 cells by treatment with Indisulam, that promote degradation of the splicing, and Pladienolide B, that impairs the activity of SF3B1.

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Splicing targeting approaches highlight actionable vulnerabilities in advanced prostate cancer [22Rv1]

Project description:To investigate if pharmacological inhibition of splicing could uncover novel actionable vulnerabilities in CRPC, we profiled the genome-wide transcriptional changes elicited in 22Rv1 cells by treatment with three drugs that inhibit the splicing through different molecular targets: i. Pladienolide B, that impairs the activity of SF3B1; ii. Indisulam that promote degradation of the splicing factor RBM39; iii. THZ531 inhibits the cyclin dependent kinases (CDK) 12 and 13.

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Splicing targeting approaches highlight actionable vulnerabilities in triple negative breast cancer

Project description:Splicing targeting approaches highlight actionable vulnerabilities in triple negative breast cancer

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Splicing targeting approaches highlight actionable vulnerabilities in advanced prostate cancer [22Rv1]

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Systematic analyses of RNA-binding proteins uncover therapeutically promising vulnerabilities in osteosarcoma

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BRD4 represses CBX5

Project description:BRD4 is amplified and/or up-regiulated in a subset of ovarian cancer which correlates with a poor survival siRNA sensitization screens in the presence of CHK1 inhibitor, LY2606368, identify BRD4 as a therapeutic target in ovarian cancer. BRD4 suppression by either siRNA or using JQ1 increases CBX5 expression

2016-05-01 | GSE78704 | GEO

Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer

Project description:Selective autophagy of mitochondria is known to promote survival and progression of cancer cells in various malignancies, including triple-negative breast cancer (TNBC). Here, we investigate the essential metabolic adaptations that support mitochondrial quality control in cancer cells with the aim to uncover therapeutically actionable metabolic vulnerabilities. Using TNBC as a model system and an integrated approach of proteomics and untargeted and stable-isotope resolved metabolomics, together with functional experimental analyses, we detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by an onco-metabolic program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle (EV)-mediated intracellular clearance of mitochondrial damage. Targeting of this sphingolipid pathway in cancer cells via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase (UGCG), resulted in ceramide-mediated compensatory mitophagy and subsequent cancer cell death in vitro and attenuated tumor growth and prolonged overall survival at clinically achievable doses in an orthotopic syngeneic mouse models of TNBC as well as in human cell-line derived xenograft models. Our study defines a mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.

2025-09-30 | PXD068183 | Pride

Targeting the Epigenetic Regulator CBX5 Promotes Fibroblast Metabolic Reprogramming and Inhibits Lung Fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is characterized by the sustained activation of interstitial fibroblasts leading to excessive collagen deposition and progressive organ failure. Epigenetic and metabolic abnormalities have been shown to contribute to the persistent activated state of scar-forming fibroblasts. However, how epigenetic changes regulate fibroblast metabolic responses to promote fibroblast activation and progressive fibrosis remains largely unknown. Here we show that the epigenetic regulator chromobox protein homolog 5 (CBX5) is critical to the transition of quiescent fibroblasts to activated collagen-producing fibroblasts in response to bleomycin injury. Loss of mesenchymal CBX5 attenuated fibrosis development, and this effect was accompanied by the downregulation of pathogenic fibroblast genes, including Cthrc1, Col1a1, and Spp1, and by the upregulation of metabolic genes with anti-fibrotic activity such as Ppara and Pparg. scRNA-seq and immunohistochemistry analyses revealed that CBX5 expression was enriched in pathogenic fibroblasts and fibroblastic foci of IPF lungs. Bulk RNA-seq analysis combined with metabolic assessments demonstrated that CBX5 silencing in IPF fibroblasts potently inhibited TGF-beta-stimulated glycolysis while enhancing AMPK signaling and mitochondrial metabolism. Finally, we showed that inhibition of the CBX5 pathway in IPF fibroblasts synergistically potentiated metformin-induced AMPK activation and IPF fibroblast quiescence. Collectively, our findings identify CBX5 as an epigenetic regulator linking metabolic maladaptation to the persistent activated state of lung fibroblasts during IPF progression.

2025-06-16 | GSE242408 | GEO

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