2018
DOI: 10.1016/j.ccell.2017.12.003
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Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase

Abstract: KRAS is a regulator of the nutrient stress response in non-small-cell lung cancer (NSCLC). Induction of the ATF4 pathway during nutrient depletion requires AKT and NRF2 downstream of KRAS. The tumor suppressor KEAP1 strongly influences the outcome of activation of this pathway during nutrient stress; loss of KEAP1 in KRAS mutant cells leads to apoptosis. Through ATF4 regulation, KRAS alters amino acid uptake and asparagine biosynthesis. The ATF4 target asparagine synthetase (ASNS) contributes to apoptotic supp… Show more

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Cited by 181 publications
(171 citation statements)
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“…In addition, SLC7A11 confers drug resistance by supplying cystine for glutathione maintenance (25)(26)(27) and represents an acquired vulnerability of MAPK inhibitor-resistant melanomas (26). Oncogenic KRAS and its effector pathways induce Nrf2, the master transcriptional regulator of endogenous antioxidant synthesis (34,47). Knockdown of KRAS or inhibition of PI3K suppresses Nrf2 activity and further regulates ATF4 (47).…”
Section: Resultsmentioning
confidence: 99%
“…In addition, SLC7A11 confers drug resistance by supplying cystine for glutathione maintenance (25)(26)(27) and represents an acquired vulnerability of MAPK inhibitor-resistant melanomas (26). Oncogenic KRAS and its effector pathways induce Nrf2, the master transcriptional regulator of endogenous antioxidant synthesis (34,47). Knockdown of KRAS or inhibition of PI3K suppresses Nrf2 activity and further regulates ATF4 (47).…”
Section: Resultsmentioning
confidence: 99%
“…Targeting of asparagine through L-asparaginase manifests in near-complete stasis of tumors that were lacking ASNS, implicating both the necessity and targetable vulnerability of KRAS-driven ASNS activity during nutrient deprivation. To this end, the combination of MK-2206, an AKT inhibitor, in combination with Lasparaginase resulted in statistically significantly reduced tumor burden of H460 xenografts in comparison to control or single agent (39).…”
Section: Asparagine Aspartate and Glutamine In Cancermentioning
confidence: 96%
“…A recently published study shows a role of asparagine in attenuating ATF4-mediated apoptosis during nutrient stress in response to KRAS signaling in non-small-cell lung cancer (NSCLC) (39). Specifically, glutamine-restriction induced KRAS-mediated upregulation of ATF4 through a KRAS-Akt-Nrf2-ATF4 axis.…”
Section: Asparagine Aspartate and Glutamine In Cancermentioning
confidence: 99%
“…In non-small-cell lung cancer expressing oncogenic KRAS, the increased ASNS expression occurs via Akt-and Nrf2-mediated induction of ATF4. Tumor growth is prevented by inhibition of Akt together with depletion of extracellular asparagine [65]. mTOR also regulates the amounts of amino acid transporters.…”
Section: Protein Synthesismentioning
confidence: 99%