Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA322185 | ENA |
REPOSITORIES: ENA
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Project description:Glutamine is a key nutrient for tumor cells that supports nucleotide and amino acid biosynthesis, replenishes the TCA cycle intermediates and contributes to redox metabolism. We identified oncogenic KRAS as a critical regulator of the response to glutamine deprivation in NSCLC. Full activation of the ATF4 stress response pathway is dependent on expression of NRF2 downstream of oncogenic KRAS in NSCLC. Through this mechanism, KRAS alters amino acid uptake and metabolism and sustains mTORC1 signaling during nutrient stress. Furthermore, we identified regulation of asparagine synthetase (ASNS) as a key effect of oncogenic KRAS signaling via ATF4 during glutamine deprivation, and a potential therapeutic target in KRAS mutant NSCLC.
2017-12-30 | GSE81643 | GEO
Project description:Glutamine is a key nutrient for tumor cells that supports nucleotide and amino acid biosynthesis, replenishes the TCA cycle intermediates and contributes to redox metabolism. We identified oncogenic KRAS as a critical regulator of the response to glutamine deprivation in NSCLC. Full activation of the ATF4 stress response pathway is dependent on expression of NRF2 downstream of oncogenic KRAS in NSCLC. Through this mechanism, KRAS alters amino acid uptake and metabolism and sustains mTORC1 signaling during nutrient stress. Furthermore, we identified regulation of asparagine synthetase (ASNS) as a key effect of oncogenic KRAS signaling via ATF4 during glutamine deprivation, and a potential therapeutic target in KRAS mutant NSCLC.
2017-12-30 | GSE81642 | GEO
Project description:Glutamine is a key nutrient for tumor cells that supports nucleotide and amino acid biosynthesis, replenishes the TCA cycle intermediates and contributes to redox metabolism. We identified oncogenic KRAS as a critical regulator of the response to glutamine deprivation in NSCLC. Full activation of the ATF4 stress response pathway is dependent on expression of NRF2 downstream of oncogenic KRAS in NSCLC. Through this mechanism, KRAS alters amino acid uptake and metabolism and sustains mTORC1 signaling during nutrient stress. Furthermore, we identified regulation of asparagine synthetase (ASNS) as a key effect of oncogenic KRAS signaling via ATF4 during glutamine deprivation, and a potential therapeutic target in KRAS mutant NSCLC.
2017-12-30 | GSE81641 | GEO
Project description:Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC
| PRJNA322181 | ENA
Project description:Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [shKRAS high Q]
| PRJNA322186 | ENA
Project description:Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [shKRAS low Q]
| PRJNA322187 | ENA
Project description:Since both KRAS mutations and LKB1 inactivating alterations affect cellular metabolism, it seems propitious to discern metabolic effects induced by the single oncogenic events from those elicited by their co-occurrence, with the ultimate aim to potentially exploit metabolic dependencies for novel therapeutic modalities. With these considerations in mind, we knocked-out the LKB1 gene in well-characterized NSCLC cell clones harboring KRAS WT or mutant G12C proteins (13,30). We obtained an isogenic system in which KRAS mutation and LKB1 inactivation were individually or concomitantly present. The effects of the genetic lesions individually or together on cell metabolism were investigated in these isogenic NSCLC cells by means of an integrated survey of proteomics, stable and dynamic metabolomics and functional in-vitro strategies.
2019-11-14 | PXD007838 | Pride
Project description:Mutant KRAS (mut-KRAS) is present in 30% of all human cancers and plays a critical role in cancer cell growth and resistance to therapy. There is evidence from colon cancer that mut-KRAS is a poor prognostic factor and negative predictor of patient response to molecularly targeted therapy. However, evidence for such a relationship in non small cell lung cancer (NSCLC) is conflicting. KRAS mutations are primarily found at codons 12 and 13, where different base changes lead to alternate amino acid substitutions that lock the protein in an active state. The patterns of mut-KRas amino acid substitutions in colon cancer and NSCLC are quite different, with aspartate (D) predominating in colon cancer (50%) and cysteine (C) in NSCLC (47%). Through an analysis of a recently completed biopsy biomarker-driven, molecularly targeted multi-arm trial of 215 evaluable patients with refractory NSCLC we show that mut-KRas-G12C/V but not total mut-KRAS predicts progression free survival for the overall group, and for the sorafenib and vandetanib treatment arms. Transcriptome microarray data shows differential expression of cell cycle genes between mut-KRas-G12C/V and G12D patient tumors. A panel of NSCLC cell lines with known mut-KRas amino acid substitutions was used to identify pathways activated by the different mut-KRas, showing that mut-KRas-G12D activates both PI-3-K and MEK signaling, while mut-KRas G12C does not, and alternatively activates RAL signaling. This finding was confirmed using immortalized human bronchial epithelial cells stably transfected with wt-KRAS and different forms of mut-KRAS. Molecular modeling studies show that the different conformation imposed by mut-KRas-G12C could lead to altered association with downstream signaling transducers compared to wild type and mut-KRas-G12D. The significance of the findings for developing mut-KRAS therapies is profound, since it suggests that not all mut-KRas amino acid substitutions signal to effectors in a similar way, and may require different therapeutic interventions. Gene expression profiles were measured in 22 core biopsies from patients with refractory non-small cell lung cancer included in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE). All tumors were KRAS mutants, but with different patterns of amino acid substitutions. Supervised analysis of transcriptome profiling was performed to compare cysteine or valine KRAS mutants with other KRAS mutants.
2012-01-01 | E-GEOD-27389 | biostudies-arrayexpress
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
Project description:Oncogenic KRAS is found in more than 25% of lung adenocarcinomas, the major histologic subtype of non–small cell lung cancer (NSCLC), and is an important target for drug development. To this end, we generated four NSCLC lines with stable knockdown selective for oncogenic KRAS. As expected, stable knockdown of oncogenic KRAS led to inhibition of in vitro and in vivo tumor growth in the KRAS-mutant NSCLC cells, but not in NSCLC cells that have wild-type KRAS (but mutant NRAS). Surprisingly, we did not see large-scale induction of cell death and the growth inhibitory effect was not complete. To further understand the ability of NSCLCs to grow despite selective removal of mutant KRAS expression, we conducted microarray expression profiling of NSCLC cell lines with or without mutant KRAS knockdown and isogenic human bronchial epithelial cell lines with and without oncogenic KRAS. We found that although the mitogen-activated protein kinase pathway is significantly downregulated after mutant KRAS knockdown, these NSCLCs showed increased levels of phospho-STAT3 and phospho–epidermal growth factor receptor, and variable changes in phospho-Akt. In addition, mutant KRAS knockdown sensitized the NSCLCs to p38 and EGFR inhibitors. Our findings suggest that targeting oncogenic KRAS by itself will not be sufficient treatment, but may offer possibilities of combining anti-KRAS strategies with other targeted drugs. Detailed information on the microarray results are available in a previous study (Sunaga N, et al. Mol Cancer Ther. 2011;10:336-46).
2024-07-16 | GSE272045 | GEO