Propionate metabolism dysregulation promotes drug-tolerant persister cell survival in non-small cell lung cancer

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 TGFB signaling. These findings reveal propionate metabolism dysregulation as a non-genetic mechanism of drug resistance and highlight propionate metabolism as a potential therapeutic target.