| RRC ID |
89144
|
| Author |
Furukawa H, Umezawa K, Sun Y, Chiba H, Kubonishi M, Naito H, Miura Y, Ito K, Aoki S.
|
| Title |
Dual targeting of glutamine metabolism and lysosomal function in eliminating drug-tolerant KRAS-mutant cancer cells.
|
| Journal |
Commun Biol
|
| Abstract |
KRAS inhibitors are reshaping the cancer-treatment landscape; however, durable responses remain limited by drug-tolerant persister cells that survive initial therapy and drive relapse. We show that KRAS-mutant pancreatic and lung cancer cells enter a reversible drug-tolerant (TR) state upon KRAS inhibition, marked by proliferative arrest and extensive metabolic adaptation. Integrated proteomic and metabolomic analyses reveal lysosome-linked remodeling and relatively broad metabolic reprogramming in TR cells. Dual blockade of glutamine metabolism and lysosome-associated processes selectively compromises TR-cell viability under KRAS inhibition, which is rescued by α-ketoglutarate (α-KG). N-acetyl-L-cysteine phenocopies the rescue, and α-KG supplementation lowers intracellular reactive oxygen species levels, supporting a model in which α-KG acts predominantly as a redox-supportive metabolite rather than a Tricarboxylic Acid Cycle intermediate, in the TR state, with lysosome-associated processes contributing to redox balance. These findings define drug-tolerant redox vulnerability and provide a rationale for co-targeting glutamine metabolism and lysosome-associated processes during KRAS inhibitor therapy.
|
| Published |
2026-5-26
|
| DOI |
10.1038/s42003-026-10374-x
|
| PII |
10.1038/s42003-026-10374-x
|
| PMID |
42191797
|
| IF |
4.165
|
| Resource |
| Human and Animal Cells |
PANC-1(RCB2095)
PK-1(RCB1972)
MIA Paca2(RCB2094) |
