Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

LKB1 inactivation elicits a NNMT-mediated methyl sink and confers dependence on PRMT5 in lung cancer

ABSTRACT: The protein arginine methyl transferase 5 (PRMT5) emerges as a therapeutic target in S-methyl-5'-thioadenosine phosphorylase (MTAP)-deleted cancers, where MTA accumulation partially inhibits its activity. However, It remains unclear whether other genetic alterations can dictate PRMT5 activity in cancer. Here we identify LKB1 as an alternative predictor of PRMT5 inhibition in lung cancer independent of MTAP. Mechanistically, LKB1 loss activates SIK1/2-CRTC2 signaling to upregulate NNMT, creating a ""methyl sink"" that lowers the SAM/SAH ratio and attenuates PRMT5 activity. NNMT overexpression is sufficient to induce this hypomorphic PRMT5 state and heighten sensitivity to PRMT5 inhibitors. Functionally, PRMT5 inhibition induces senescence in LKB1-deficient cells and confers vulnerability to navitoclax, synergistically blunting tumor growth in vivo. Collectively, we identify PRMT5 as an actionable therapeutic vulnerability in LKB1-deficient lung cancer, and propose LKB1 status/NNMT expression as potential biomarkers for PRMT5 inhibition. These findings may expand the clinical utility of PRMT5-targeted therapies beyond MTAP-deleted cancers.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic

PROVIDER: MTBLS14411 | MetaboLights | 2026-04-30

REPOSITORIES: MetaboLights

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	a_MTBLS14411_LC-MS_positive_hilic.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14411_LC-MS_positive_hilic_v2_maf.tsv	Tabular
	s_MTBLS14411.txt	Txt

Items per page:

1 - 4 of 4

Similar Datasets

Expression data from Hif 2alpha Knockdown study

Project description:Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. The oxygen-sensitive Hypoxia Inducible Factor (HIF) transcriptional regulators HIF-1Î± and HIF-2Î± are overexpressed in many human NSCLCs, and constitutive HIF-2Î± activity can promote murine lung tumor progression, suggesting that HIF proteins may be effective NSCLC therapeutic targets. To investigate the consequences of inhibiting HIF activity in lung cancers, we deleted Hif-1Î± or Hif-2Î± in an established KrasG12D-driven murine NSCLC model. Deletion of Hif-1Î± had no obvious effect on tumor growth, whereas Hif-2Î± deletion resulted in an unexpected increase in tumor burden that correlated with reduced expression of the candidate tumor suppressor gene Scgb3a1 (HIN-1). Here, we identify Scgb3a1 as a direct HIF-2Î± target gene, and demonstrate that HIF-2Î± regulates Scgb3a1 expression and tumor formation in human KrasG12D-driven NSCLC cells. AKT pathway activity, reported to be repressed by Scgb3a1, was enhanced in HIF-2Î± deficient human NSCLC cells and xenografts. Finally, a direct correlation between HIF-2Î± and SCGB3a1 expression was observed in approximately 70% of human NSCLC samples analyzed. These data suggest that whereas HIF-2Î± overexpression can contribute to NSCLC progression, therapeutic inhibition of HIF-2Î± below a critical threshold may paradoxically promote tumor growth by reducing expression of tumor suppressor genes, including Scgb3a1. RNA was isolated from tumors of experimental (Hif2alpha deficient) mice and control mice (seven for each group).

2010-07-29 | E-GEOD-22575 | biostudies-arrayexpress

BRG1 loss predisposes lung cancers to replicative stress and ATR dependency

Project description:Gupta M, Concepcion CP, Fahey CG, Keshishian H, Bhutkar A, Brainson CF, Sanchez-Rivera FJ, Pessina P, Kim JY, Simoneau A, Paschini M, Beytagh MC, Stanclift C, Schenone M, Mani DR, Li C, Oh A, Li F, Hu H, Karatza A, Bronson RT, Shaw AT, Hata AN, Wong K, Zou L, Carr SA, Jacks T, Kim CF. Cancer Res 2020. Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non-small cell lung cancers. There are no targeted therapies for this subset of lung cancers, nor is it known how mutations in BRG1 contribute to lung cancer progression. Using a combination of gain- and loss-of-function approaches, we demonstrate that deletion of BRG1 in lung cancer leads to activation of replication stress responses. Single-molecule assessment of replication fork dynamics in BRG1-deficient cells revealed increased origin firing, mediated through pre-licensing protein CDC6. Quantitative mass spectrometry and co-immunoprecipitation assays showed that BRG1-containing SWI/SNF complexes interact with RPA complexes. Lastly, we show that BRG1-deficient lung cancers are sensitive to the pharmacological inhibition of ATR. These findings provide novel mechanistic insight into BRG1-mutant lung cancers and suggest that their ATR dependency can be leveraged therapeutically, and potentially expanded to BRG1- mutant cancers in other tissues.

2020-07-08 | MSV000085701 | MassIVE

Inhibition of TGFβRI as a therapy for GATA4 deficient lung cancers

Project description:Inhibition of TGFβRI as a therapy for GATA4 deficient lung cancers

| PRJNA335852 | ENA

Proteome wide analysis of NRF2 activation

Project description:Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers, however the role of this pathway in cancers with wildtype KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines—an effect that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.

2024-05-24 | PXD039027 | Pride

Expression data from Hif 2alpha Knockdown study

Project description:Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. The oxygen-sensitive Hypoxia Inducible Factor (HIF) transcriptional regulators HIF-1α and HIF-2α are overexpressed in many human NSCLCs, and constitutive HIF-2α activity can promote murine lung tumor progression, suggesting that HIF proteins may be effective NSCLC therapeutic targets. To investigate the consequences of inhibiting HIF activity in lung cancers, we deleted Hif-1α or Hif-2α in an established KrasG12D-driven murine NSCLC model. Deletion of Hif-1α had no obvious effect on tumor growth, whereas Hif-2α deletion resulted in an unexpected increase in tumor burden that correlated with reduced expression of the candidate tumor suppressor gene Scgb3a1 (HIN-1). Here, we identify Scgb3a1 as a direct HIF-2α target gene, and demonstrate that HIF-2α regulates Scgb3a1 expression and tumor formation in human KrasG12D-driven NSCLC cells. AKT pathway activity, reported to be repressed by Scgb3a1, was enhanced in HIF-2α deficient human NSCLC cells and xenografts. Finally, a direct correlation between HIF-2α and SCGB3a1 expression was observed in approximately 70% of human NSCLC samples analyzed. These data suggest that whereas HIF-2α overexpression can contribute to NSCLC progression, therapeutic inhibition of HIF-2α below a critical threshold may paradoxically promote tumor growth by reducing expression of tumor suppressor genes, including Scgb3a1.

2010-06-28 | GSE22575 | GEO

Effect of PRMT5i (MRTX1719), ERKi (Adagrasib), RAFi (Belvarafenib) and their combination on non-small cell lung cancer cell line (LU99)

Project description:CDKN2A/MTAP co-deletion occurs frequently in non-small cell lung cancer and other solid tumors including glioblastoma and pancreatic ductal adenocarcinoma. Lung cancer remains the leading cause of cancer-related mortalities and fewer than 15% of glioblastoma or pancreatic cancer patients survive 5 years underscoring the need for more effective therapies. PRMT5 is a synthetic-lethal dependency in MTAP null tumors and an attractive therapeutic target for CDKN2A/MTAP deleted cancers. A new revolutionary class of inhibitors, referred to as MTA-cooperative PRMT5 inhibitors, has shown promising results in ongoing early phase clinical trials. Nonetheless, effective cancer treatment typically requires therapeutic combinations to improve response rates and defeat emergent resistant clones. Thus, we sought to determine whether perturbation of other pathways could improve the efficacy of MTA-cooperative PRMT5 inhibitors. Using a paralog and single gene targeting CRISPR library we screened MTAP deleted cancers in the presence or absence of PRMT5 inhibitors. We identified several genes sensitizing to PRMT5 inhibition including members of the MAP kinase pathway. We demonstrate that genetic depletion or chemical inhibition of MAP kinase pathway members using KRAS, MEK, ERK, and RAF inhibitors synergize with PRMT5 inhibition to kill CDKN2A/MTAP null, RAS-active tumors. Further, PRMT5 inhibitors combined with either KRAS or RAF inhibitors durable in vivo complete responses, emphasizing the potential benefit for patients.

2025-07-13 | GSE282795 | GEO

Effect of PRMT5i (MRTX1719) on glioblastoma cell line (A172)

2025-07-13 | GSE282794 | GEO

BCL6 is regulated by the RAS/MAPK/ELK axis and promotes KRAS-driven lung cancers

Project description:Mutational activation of KRAS represents a common oncogenic event in lung cancers and still lacks effective treatments so far. Here, we identify the proto-oncogene B-cell lymphoma 6 (BCL6) as a lynchpin for KRAS dependence. BCL6 transcription was markedly promoted upon inducible activation of KRAS in either LSL-KrasG12D mice lung tumor tissue or engineered KRAS isogenic cell lines. Constitutive expression of BCL6 was also observed in patients with KRAS-mutant lung adenocarcinoma and associated with poor survival. Employing chemical and genetic screens, we characterized that the MAPK/ELK1 axis downstream of KRAS directly regulated BCL6 expression. Genetic depletion or pharmacological inhibitor targeting BCL6 preferentially impedes the proliferation of KRAS-mutant lung cancer cells by suppressing pre-RC protein expression in cycling cells, ultimately leading to stalled replication and DNA damage in vitro. Accordingly, targeted inhibition of BCL6 significantly reduced tumor burden and mortality in LSL-KrasG12D/+ and patient-derived lung cancer xenograft mouse models in vivo. Taken together, these findings reveal an oncogenic role of BCL6 in promoting KRAS-addicted lung cancers and define that BCL6 inhibition confers a targetable vulnerability for this kind of disease.

2022-10-19 | GSE189545 | GEO

MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP deleted cancer

Project description:Previous studies implicated PRMT5 as a synthetic lethal target for MTAP deleted (MTAP del) cancers, however, the pharmacological characterization of small molecule inhibitors that recapitulate the synthetic lethal phenotype have not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selectivity in HCT116 MTAP del compared to HCT116 MTAP WT cells. MRTX1719 demonstrated dose-dependent anti-tumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts, mouse or human hematopoietic cells. MRTX1719 demonstrated marked anti-tumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and MPNST from the Phase 1/2 study. Significance: PRMT5 was identified as a synthetic lethal target for MTAP del cancers, however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ~10% of cancer patients with this biomarker.

2023-08-09 | GSE240145 | GEO

Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes: a Proof-of-Concept synthetic lethal study

Project description:An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which binds multiple binding partners to suppress tumourigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD11, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of ‘druggable’ targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify synthetic lethal compounds with LIMD1 loss in lung cancer cells. PF-477736 was shown to selectively target LIMD1 deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 is effective in treating LIMD1-/- tumors in subcutaneous xenograft models, with no significant effect in LIMD1+/+ cells. We have identified a novel drug tool with significant preclinical characterization that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.

2022-02-16 | PXD023674 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data