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<p>Recent studies show that genetic sequencing can not fully explain drug resistance in non-small cell lung cancer (NSCLC), suggesting undiscovered non-genetic mechanisms that can enable cancer cell survival. Propionate metabolism is the pathway by which odd-chain fatty acids, branched chain amino acids, and cholesterol are metabolized. We have previously shown that methylmalonic acid (MMA), a byproduct of propionate metabolism that accumulates when the pathway is disrupted, can activate epithelial-to-mesenchymal transition (EMT) in cell lines. But the clinical significance of propionate metabolism in cancer patients is not known. Here we show, for the first time, that propionate metabolism is dysregulated in patients with non-small cell lung cancer. MMA is elevated in lung tumors and in the serum of patients with metastatic NSCLC. Metabolism of cobalamin associated B (MMAB), a key regulatory gene of propionate metabolism, is downregulated in NSCLC and drug-tolerant persister cells, leading to MMA accumulation and EMT activation. We show that restoring expression of MMAB in NSCLC enhances targeted therapy and suppresses TGFβ signaling. These findings reveal propionate metabolism dysregulation as a non-genetic mechanism of drug resistance and highlight propionate metabolism as a potential therapeutic target.</p>

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Propionate metabolism is dysregulated in non-small cell lung cancer patients and EGFR-mutant drug-tolerant persister cells

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月18日

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  • Bobak Parang,
  • Liron Yoffe,
  • Rabia Khan,
  • Zhongchi Li,
  • Michal J. Nagiec,
  • Eric E. Gardner,
  • Yiwey Shieh,
  • Rachel S. Heise,
  • Ashish Saxena,
  • Nasser Altorki,
  • John Blenis

摘要

Recent studies show that genetic sequencing can not fully explain drug resistance in non-small cell lung cancer (NSCLC), suggesting undiscovered non-genetic mechanisms that can enable cancer cell survival. Propionate metabolism is the pathway by which odd-chain fatty acids, branched chain amino acids, and cholesterol are metabolized. We have previously shown that methylmalonic acid (MMA), a byproduct of propionate metabolism that accumulates when the pathway is disrupted, can activate epithelial-to-mesenchymal transition (EMT) in cell lines. But the clinical significance of propionate metabolism in cancer patients is not known. Here we show, for the first time, that propionate metabolism is dysregulated in patients with non-small cell lung cancer. MMA is elevated in lung tumors and in the serum of patients with metastatic NSCLC. Metabolism of cobalamin associated B (MMAB), a key regulatory gene of propionate metabolism, is downregulated in NSCLC and drug-tolerant persister cells, leading to MMA accumulation and EMT activation. We show that restoring expression of MMAB in NSCLC enhances targeted therapy and suppresses TGFβ signaling. These findings reveal propionate metabolism dysregulation as a non-genetic mechanism of drug resistance and highlight propionate metabolism as a potential therapeutic target.