論文 - 詳細
| RRC ID | 86343 |
|---|---|
| 著者 | Zhang H, Santana-Codina N, Yu Q, Poupault C, Campos C, Qin X, Sindoni N, Ciscar M, Padhye A, Kuljanin M, Wang J, Dorman MJ, Bross P, Aguirre AJ, Dougan SK, Sarosiek KA, Mancias JD. |
| タイトル | De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer. |
| ジャーナル | Nat Commun |
| Abstract |
Oncogenic KRAS induces metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC) characterized, in part, by dependency on de novo pyrimidine biosynthesis. Pharmacologic inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, delays pancreatic tumor growth; however, limited monotherapy efficacy suggests that compensatory pathways may drive resistance. Here, we use an integrated metabolomic, proteomic and in vitro and in vivo DHODH inhibitor-anchored genetic screening approach to identify compensatory pathways to DHODH inhibition (DHODHi) and targets for combination therapy strategies. We demonstrate that DHODHi alters the apoptotic regulatory proteome thereby enhancing sensitivity to inhibitors of the anti-apoptotic BCL2L1 (BCL-XL) protein. Co-targeting DHODH and BCL-XL synergistically induces apoptosis in PDAC cells and patient-derived organoids. The combination of DHODH inhibition with Brequinar and BCL-XL degradation by DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits PDAC tumor growth. These data define mechanisms of adaptation to DHODHi and support combination therapy targeting BCL-XL in PDAC. |
| 巻・号 | 16(1) |
| ページ | 6987 |
| 公開日 | 2025-7-30 |
| DOI | 10.1038/s41467-025-61242-x |
| PII | 10.1038/s41467-025-61242-x |
| PMID | 40738904 |
| PMC | PMC12311037 |
| MeSH | Animals Apoptosis / drug effects Biphenyl Compounds / pharmacology Carcinoma, Pancreatic Ductal* / drug therapy Carcinoma, Pancreatic Ductal* / genetics Carcinoma, Pancreatic Ductal* / metabolism Carcinoma, Pancreatic Ductal* / pathology Cell Line, Tumor Dihydroorotate Dehydrogenase Drug Synergism Humans Mice Oxidoreductases Acting on CH-CH Group Donors* / antagonists & inhibitors Oxidoreductases Acting on CH-CH Group Donors* / genetics Oxidoreductases Acting on CH-CH Group Donors* / metabolism Pancreatic Neoplasms* / drug therapy Pancreatic Neoplasms* / genetics Pancreatic Neoplasms* / metabolism Pancreatic Neoplasms* / pathology Proteomics Pyrimidines* / biosynthesis Quinaldines Xenograft Model Antitumor Assays bcl-X Protein* / antagonists & inhibitors bcl-X Protein* / genetics bcl-X Protein* / metabolism |
| IF | 12.121 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 19 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | PK-1(RCB1972) KP-4(RCB1005) |