SLC15A3-Mediated Dipeptide Metabolism Confers Antimetabolite Resistance in Lymphoma via mTORC1 Activation [Ribo-seq]

However, the underlying mechanisms of this resistance have long remained elusive. Using an innovative, integrated omics approach, we unexpectedly identified that the accumulation of dipeptides and upregulation of the dipeptide transporter SLC15A3 underlie resistance to nucleotide deficiency in a Myc-driven large B cell lymphoma mouse model.

A similar mechanism occurs after long treatment of human B cell lymphoma cells with the chemotherapeutic purine synthesis inhibitor 6-mercaptopurine (6MP). Mechanistically, we demonstrate that dipeptides containing essential amino acids activate the growth and survival mTORC1 signaling pathway. Notably, SLC15A3 specifically interacts with mTOR on the lysosome, boosting mTORC1 activity selectively in resistant lymphoma cells but not in the parental cancer cells.