Table 3.
KRAS and amino acid metabolism in cancer
| Cancer type | Targeting | Function and Mechanism | Ref |
|---|---|---|---|
| PDAC | OAT | KRAS drives DNS and polyamine synthesis via induction of OAT, leading to alterations in the transcriptome and open chromatin landscape in PDAC cells. | [89] |
| PDAC | DON | DON and DRP-104 reduce oxidative phosphorylation, glycolysis and TCA cycle, which resulting in inhibiting PDAC tumor development. | [90] |
| PDAC | MDH1 | Depletion of O-GlcNAcylation reduces MDH1 activity, impairs glutamine metabolism and sensitizes KRAS mutant PDAC cells to oxidative stress. | [91] |
| PDAC | BCAA, BCAT2 | BCAT2 is essential for KRAS G12D PDAC by increasing BCAA uptake. | [92] |
| PDAC, CRC | – | Restriction of dietary serine and glycine reduces tumour growth in xenograft and allograft models, however, KRAS G12D confers resistance to the anti-cancer effects. | [93] |
| CRC | SLC25A21 | KRAS mutant promotes CRC tumorigenesis by downregulation of SLC25A21 and αketoglutarate. | [94] |
| CRC | SLC25A22 | SLC25A22-mediated glutamine metabolism enhances CXCL1 chemokines level via asparagine biosynthesis to promote KRAS-mutant CRC. | [95] |
| CRC | YAP1 | Oncogenic KRAS mutations enhance AAT expression through the hippo effector YAP1, leading to mTOR activation and CRC cell proliferation. | [96] |
| NSCLC | SLC7A1 | Inhibition of ASS1 in KRAS mutant NSCLC cells affects arginine biosynthesis, resulting in a dependence of extracellular arginine input on the arginine transmembrane transporter protein SLC7A1. | [97] |
| NSCLC | ATF4 | NRF2-mediated ATF4 contributes KRAS-induced amino acid transport and metabolism. | [98] |
| LUAD | STAT3 | pS727-STAT3 enhance KRAS-induced LUAD development by impairing mitochondrial metabolism. | [99] |
| LUAD | SLC7A11 | The SLC7A11 inhibitor HG106 suppresses cystine uptake and intracellular glutathione biosynthesis, impairing tumor growth and promoting beneficial outcome. | [100] |
| LUAD | NRF2 | NRF2/KEAP1 and LKB1 loss cooperatively rewire metabolism and enhance glutaminase inhibitor CB-839 sensitivity in lung cancer. | [101] |
| – | – | Synergy between LKB1 loss and KRAS mutations enhances de novo serine biosynthesis and supports tumor growths. | [102] |
Abbreviations
PDAC pancreatic ductal adenocarcinoma, OAT ornithine aminotransferase, ODC1 ornithine decarboxylase 1, DON 6-diazo-5-oxoL-norleucine, DRP-104 sirpiglenastat, MDH1 Malate dehydrogenase 1, BCAA branched-chain amino acid, BCAT2 BCAA transaminase 2, O-GlcNAcylation O-linked β-N-acetylglucosamine, CRC colorectal cancer, SLC25A21 solute carrier family 25 member 21, SLC25A22 solute carrier family 25 member 22, YAP1 yes1 associated transcriptional regulator, AAT amino acid transporters (SLC7A5/LAT1, SLC38A2/SNAT2, and SLC1A5/ASCT2), mTOR mechanistic target of rapamycin, NSCLC non-small cell lung cancer, SLC7A1 solute carrier family 7 member 1, ASS1 arginine succinate synthase 1, ATF4 activating transcription factor 4, NRF2 nuclear factor erythroid 2-related factor 2, LUAD lung adenocarcinoma, STAT3 signal transducer and activator of transcription 3, SLC7A11 solute carrier family 7 member 11, KEAP1 Kelch Like ECH Associated Protein 1, LKB1 liver kinase B1