Reference - Detail
| RRC ID | 86223 |
|---|---|
| Author | Pan YQ, Han Y, Qian ZY, Zhang XY, Wang TT, Cai ZR, Chen H, Li Y, Liao K, Zheng YQ, Zhang YY, Wu QN, Wu HX, Tian T, Chen W, Chen Y, Zeng ZL, Liu ZX, Piao HL, Guan XY, Xu RH, Ju HQ. |
| Title | A preserved TGFβ cytostatic response through DLD-mediated metabolic modulation undermines anti-TGFβ therapy in gastric cancer. |
| Journal | Nat Commun |
| Abstract |
Despite the well-known role of the transforming growth factor-β (TGFβ) pathway in cancer progression, therapies targeting it have largely failed in the clinic. This suggests our understanding of TGFβ's function is incomplete. Here we show that this therapeutic failure is rooted in a fundamental paradox: while TGFβ promotes malignant traits in gastric cancer, many cancer cells remain sensitive to its potent tumor-suppressive effects. We uncover that this suppression works by impairing the cell's energy metabolism through modulating dihydrolipoamide dehydrogenase (DLD). Therefore, broadly blocking the TGFβ pathway can inadvertently release a natural brake on tumor growth. Based on this insight, we demonstrate that co-targeting this metabolic vulnerability with an inhibitor (devimistat) alongside an anti-TGFβ agent significantly enhances therapeutic efficacy in gastric cancer models. This combination approach presents a promising strategy to overcome the limitations of current therapies. |
| Volume | 16(1) |
| Pages | 10016 |
| Published | 2025-11-14 |
| DOI | 10.1038/s41467-025-64997-5 |
| PII | 10.1038/s41467-025-64997-5 |
| PMID | 41238541 |
| PMC | PMC12618484 |
| MeSH | Animals Benzamides / pharmacology Cell Line, Tumor Cell Proliferation / drug effects Energy Metabolism / drug effects Female Humans Mice Mice, Nude Pyrazoles Quinolines Signal Transduction / drug effects Stomach Neoplasms* / drug therapy Stomach Neoplasms* / metabolism Stomach Neoplasms* / pathology Transforming Growth Factor beta* / antagonists & inhibitors Transforming Growth Factor beta* / metabolism Xenograft Model Antitumor Assays |
| IF | 12.121 |
| Resource | |
| Human and Animal Cells | MKN45(RCB1001) MKN74(RCB1002) |