SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation

Resistance to antimetabolites, a cornerstone of chemotherapy targeting nucleotide biosynthesis, remains a significant challenge in treating B cell lymphomas. Despite their widespread use, the mechanisms underlying this resistance have been largely elusive, limiting the development of effective strategies for patients whose cancers no longer respond. Understanding these metabolic adaptations is crucial for identifying novel therapeutic targets and improving outcomes in drug-resistant lymphoma.

Researchers employed an integrated omics approach in a Myc-driven large B cell lymphoma mouse model and human B cell lymphoma cell lines. They induced resistance by long-term treatment with the purine synthesis inhibitor 6-mercaptopurine (6MP). Key experiments involved silencing SLC15A3 expression and treating resistant cells and mice with the clinical mTOR inhibitor, rapamycin, both in culture and in vivo. Human lymphoma biopsies were also analyzed for SLC15A3 expression following antimetabolite therapy.

The study unexpectedly identified that accumulation of dipeptides and upregulation of the dipeptide transporter SLC15A3 are central to resistance against nucleotide deficiency in lymphoma. This mechanism was observed in both mouse models and human B cell lymphoma cells treated with 6MP. Mechanistically, dipeptides containing essential amino acids were found to activate the growth and survival mTOR complex 1 (mTORC1) signaling pathway. Notably, SLC15A3 specifically interacted with mTOR on the lysosome, leading to a selective boost in mTORC1 activity in resistant lymphoma cells, but not in parental cancer cells. Silencing SLC15A3 diminished mTORC1 activity and restored the sensitivity of resistant lymphoma cells to 6MP. Strikingly, resistant lymphomas, unlike primary tumors, exhibited heightened sensitivity to the clinical mTOR inhibitor, rapamycin, both in culture and in vivo. Human lymphoma biopsies further corroborated these findings, showing increased SLC15A3 expression after antimetabolite therapy. This suggests a conserved metabolic adaptation.