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Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [low versus high Q]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE81641 | GEO | 2017/12/30

SECONDARY ACCESSION(S): PRJNA322185

REPOSITORIES: GEO

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Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [shKRAS low Q]

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.

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Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [shKRAS high Q]

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Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC

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Project description:Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [shKRAS low Q]

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Project description:Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [shKRAS high Q]

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Microarray expression data of NCI-H1975 cells treated with osimertinib, alpelisib, or combination of these in the presence or absence of L-histidinol.

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Project description:Oncogenic KRAS mediates amino acid metabolism during nutrient stress via regulation of NRF2 and ATF4 in NSCLC [low versus high Q]

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