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Oncogenic KRAS induces arginine auxotrophy in non-small cell lung cancer and confers a therapeutic vulnerability to SLC7A1 inhibition

ABSTRACT: Oncogenic KRAS induces arginine auxotrophy in non-small cell lung cancer and confers a therapeutic vulnerability to SLC7A1 inhibition

PROVIDER: PRJNA1066766 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27646828_1.fastq.gz	Fastqsanger.gz
	SRR27646828_2.fastq.gz	Fastqsanger.gz
	SRR27646829_1.fastq.gz	Fastqsanger.gz
	SRR27646829_2.fastq.gz	Fastqsanger.gz
	SRR27646830_1.fastq.gz	Fastqsanger.gz

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Oncogenic KRAS induces arginine auxotrophy in non-small cell lung cancer and confers a therapeutic vulnerability to SLC7A1 inhibition

Project description:The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer, yet our understanding about the regulatory mechanisms for this pathway in different types of cancer is very limited. In this study, we discover that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silences the expression of arginosuccinate synthase 1 (ASS1), a urea cycle enzyme catalyzing the production of arginine from aspartate and citrulline, and thereby diverts the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication in KRAS-mutant NSCLC. Specifically, KRAS signaling facilitates a hypo-acetylated state in the promoter region of ASS1 gene in a histone deacetylase 3 (HDAC3)-dependent manner, which in turn impedes the recruitment of the transcription factor c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cancer cells impairs the biosynthesis of arginine and renders growth dependency on SLC7A1, an arginine transmembrane transport, to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models obtains a substantial therapeutic benefit in inhibiting KRAS-driven NSCLC growth. Together, our findings uncover a new role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability in treating KRAS-mutant NSCLC.

2024-01-20 | GSE253688 | GEO

A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers

Project description:A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers

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A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers [HOXC10]

Project description:A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers [HOXC10]

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A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers [inhibitors]

Project description:A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS mutant lung cancers [inhibitors]

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Protein Arginine Methyltransferase 1 is therapeutic vulnerability in Multiple Myeloma

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BCL6 confers KRAS-mutant NSCLCs resistance to BET inhibitors

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Oncogenic KRAS confers chemoresistance by upregulating NRF2.

Project description:Oncogenic KRAS mutations found in 20% to 30% of all non-small cell lung cancers (NSCLC) are associated with chemoresistance and poor prognosis. Here we demonstrate that activation of the cell protective stress response gene NRF2 by KRAS is responsible for its ability to promote drug resistance. RNAi-mediated silencing of NRF2 was sufficient to reverse resistance to cisplatin elicited by ectopic expression of oncogenic KRAS in NSCLC cells. Mechanistically, KRAS increased NRF2 gene transcription through a TPA response element (TRE) located in a regulatory region in exon 1 of NRF2. In a mouse model of mutant KrasG12D-induced lung cancer, we found that suppressing the NRF2 pathway with the chemical inhibitor brusatol enhanced the antitumor efficacy of cisplatin. Cotreatment reduced tumor burden and improved survival. Our findings illuminate the mechanistic details of KRAS-mediated drug resistance and provide a preclinical rationale to improve the management of lung tumors harboring KRAS mutations with NRF2 pathway inhibitors.

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Transcription profiling of human lung epithelial cells ollowing oncogenic KRAS expression and TBK1 suppression or infection with oncogenic KRAS (G12V) - SuperSeries

Project description:The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. This SuperSeries is composed of the following subset Series:; GSE17643: Profiling of immortalized human lung epithelial cells following oncogenic KRAS expression and TBK1 suppression; GSE17671: Profiling of immortalized human lung epithelial cells following infection with oncogenic KRAS (G12V) Experiment Overall Design: Refer to individual Series

2009-10-31 | E-GEOD-17672 | biostudies-arrayexpress

The ISR activation confers vulnerability to mitoribosome-targeting antibiotics in melanoma

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Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction

Project description:Defective arginine synthesis, due to the silencing of argininosuccinate synthase 1 (ASS1), is a common metabolic vulnerability in cancer, known as arginine auxotrophy. Understanding how arginine depletion kills arginine-auxotrophic cancer cells will facilitate the development of anti-cancer therapeutic strategies. Here we show that depletion of extracellular arginine in arginine-auxotrophic cancer cells causes mitochondrial distress and transcriptional reprogramming. Mechanistically, arginine starvation induces asparagine synthetase (ASNS), depleting these cancer cells of aspartate, and disrupting their malate-aspartate shuttle. Supplementation of aspartate, depletion of mitochondria, and knockdown of ASNS all protect the arginine-starved cells, establishing the causal effects of aspartate depletion and mitochondrial dysfunction on the arginine starvation-induced cell death. Furthermore, dietary arginine restriction reduced tumor growth in a xenograft model of ASS1-deficient breast cancer. Our data challenge the view that ASNS promotes homeostasis, arguing instead that ASNS-induced aspartate depletion promotes cytotoxicity, which can be exploited for anti-cancer therapies.

2019-11-07 | MTBLS745 | MetaboLights

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