SLC15A3-mediated dipeptide import sustains mTORC1 activation in B cell lymphomas, enabling resistance to antimetabolite chemotherapy; inhibiting SLC15A3 or mTORC1 restores drug sensitivity.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | Lymphoma cell lines / mouse |
| Journal | Journal of Clinical Investigation |
| Year | 2026 |
| Peer reviewed | Yes |
| Source | DOI 10.1172/JCI199709 · PMID 42454485 · Free full text (PMC13367966) |
Antimetabolite chemotherapy resistance is a major barrier in B cell lymphoma. This study demonstrates that SLC15A3, a dipeptide transporter, mediates import of dipeptides that sustain mTORC1 activation in lymphoma cells, providing a metabolic route to antimetabolite resistance independent of de novo nucleotide synthesis. SLC15A3 inhibition resensitized resistant lymphoma cells to antimetabolite treatment.
| Intervention | SLC15A3 inhibition; mTORC1 inhibition |
| Target | mTORC1; SLC15A3 dipeptide transporter; nutrient sensing |
| Model | Mouse; human lymphoma cell lines |
| Effect | SLC15A3 imports dipeptides to activate mTORC1, conferring antimetabolite chemoresistance; SLC15A3 or mTORC1 inhibition reverses resistance |