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Mechanism of TP53 and RB1 inactivation-induced neuroendocrine phenotype transformation in TKI-resistant lung adenocarcinoma

ABSTRACT: Mechanism of TP53 and RB1 inactivation-induced neuroendocrine phenotype transformation in TKI-resistant lung adenocarcinoma

PROVIDER: PRJNA971899 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24520512_1.fastq.gz	Fastqsanger.gz
	SRR24520512_2.fastq.gz	Fastqsanger.gz
	SRR24520513_1.fastq.gz	Fastqsanger.gz
	SRR24520513_2.fastq.gz	Fastqsanger.gz
	SRR24520514_1.fastq.gz	Fastqsanger.gz

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Mechanism of TP53 and RB1 inactivation-induced neuroendocrine phenotype transformation in TKI-resistant lung adenocarcinoma

Project description:In order to study the mechanism of co-inactivation of RB1 and TP53 in the transformation of lung adenocarcinoma to small cell lung cancer, we established the NCI-H1975 cell line with RB1 knockdown.NCI-H1975 cells were cultured and infected with lentivirus expressing RB1-shRNA (n=3) or pLKO.1-shRNA (n=3), We then performed transcriptome sequencing (RNA-seq) on the above cells.

2023-08-20 | PXD042073 | Pride

Mechanism of TP53 and RB1 inactivation-induced neuroendocrine phenotype transformation in TKI-resistant lung adenocarcinoma

2023-07-25 | GSE232387 | GEO

Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Broad Spectrum of Cancer Therapeutics and Confers Vulnerability to Replication Stress

Project description:Prostate cancers (PC) with loss of the potent tumor suppressors TP53 and RB1 exhibit poor outcomes that include resistance to androgen receptor (AR) pathway antagonists. TP53 and RB1 also influence cell plasticity and are frequently lost in PCs with neuroendocrine (NE) differentiation. Therapeutic strategies that address these aggressive variant PCs are urgently needed. Using deep genomic profiling of 410 metastatic biopsies, we determined the relationships between combined TP53 and RB1 loss and PC phenotypes. Notably, 40% of TP53/RB1 deficient tumors were classified as AR-active adenocarcinomas indicating that NE differentiation is not an obligate consequence of TP53/RB1 inactivation. A gene expression signature reflecting TP53/RB1 loss was associated with diminished responses to AR antagonists and reduced survival. These tumors exhibit high proliferation rates and evidence of elevated DNA repair processes. While tumor cells lacking TP53/RB1 were highly resistant to all single agent therapeutics, the combination of pharmacological PARP and ATR inhibition produced significant responses, reflecting a clinically-exploitable vulnerability resulting from replication stress.

2020-06-01 | GSE147250 | GEO

Neuropilin-2 axis in regulating secretory phenotype of neuroendocrine-like prostate cancer cells: implication in therapy resistance

Project description:Gene expression was first compared between prostate adenocarcinoma cell line LNCaP C4-2 and our developed neuroendocrine like derived cell line DKD (LNCaP C4-2 stably depleted with TP53 and RB1). In the next set, we compared the gene expression of neuroendocrine like DKD under presence and absence of Neurolipilin-2.

2022-05-09 | GSE202299 | GEO

RB1 expression and targeting by CDK4/6 inhibitors in small cell lung cancer

Project description:The canonical model of small cell lung cancer (SCLC) depicts tumors arising from dual inactivation of TP53 and RB1. However, many genomic studies have persistently identified tumors with no RB1 mutations. Here, we examined RB1 protein expression and function in SCLC. RB1 expression was examined by immunohistochemical analysis of 62 human SCLC tumors. These studies showed that ~14% of SCLC tumors expressed abundant RB1 protein, which is associated with neuroendocrine (NE) gene expression and is enriched in YAP1 expression, but no other lineage proteins that stratify SCLC. SCLC cells and xenograft tumors with RB1 protein expression were sensitive to growth inhibition by the CDK4/6 inhibitor palbociclib, and this inhibition was shown to be dependent on RB1 expression by CRISPR knockout. Furthermore, a patient with biopsy-validated wt RB1 SCLC who received the CDK4/6 inhibitor abemaciclib demonstrated a dramatic decrease in mutant TP53 ctDNA allelic fraction from 62.1% to 0.4% and decreased tumor mass on CT scans. Importantly, immunohistochemistry of the diagnostic biopsy specimen showed RB1 positivity. Finally, we identified a transcriptomics-based RB1 loss-of-function signature that discriminates between SCLC cells with or without RB1 protein expression and validated it in the patient who was responsive to abemaciclib, suggesting its potential use to predict CDK4/6 inhibitor response in SCLC patients. Our study demonstrates that RB1 protein is an actionable target in a subgroup of SCLC, a cancer that exhibits no currently targetable mutations.

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Project description:TKI

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RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner

Project description:Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNETs) that correlated with high level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor suppressor pathways in the arrested cells. Specific inactivation of p53 had no effect on the RABL6A knockdown phenotype, indicating RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation restored G1 to S phase progression in RABL6A knockdown cells although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a new negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients. Total RNA obtained from human BON-1 PNET cells with RABL6A shRNA knockdown compared to BON-1 cells expressing control vector.

2014-07-01 | E-GEOD-53778 | biostudies-arrayexpress

Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 downregulation in lung and prostate cancers [RNA-seq]

Project description:In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here we explored the role of exportin 1 in NE transformation. We observed upregulated exportin 1 in lung and prostate pre-transformation adenocarcinomas. Exportin 1 was induced upregulated following genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation and extended response to targeted therapies in both lung anddifferent TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the AR inhibitor enzalutamide, and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE transformationNE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs tumors after NE transformation to standard cytotoxics. Together these data nominate exportin 1 inhibition as a novel potential therapeutic approach target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma.

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Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 downregulation in lung and prostate cancers [ATAC-seq]

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Transcriptomic analysis of lung cancers arising following deletion of Tp53, Rb1 and overexpression of MYC in distinct adult mouse lung eptithelial cell lineages

Project description:Profile of the transcriptomics of tumours arising in the mouse lung following deletion of Rb1, Trp53 and overexpression of MYC from neuroendocrine cells, club cells, AT2 cells or throughout the lung epithelium.

2021-10-25 | GSE161185 | GEO

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