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<p>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.</p><p></p>

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Dual targeting of glutamine metabolism and lysosomal function in eliminating drug-tolerant KRAS-mutant cancer cells

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月26日

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  • Hiroki Furukawa,
  • Keitaro Umezawa,
  • Yuchen Sun,
  • Hinata Chiba,
  • Marin Kubonishi,
  • Hayato Naito,
  • Yuri Miura,
  • Kousei Ito,
  • Shigeki Aoki

摘要

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.