| RRC ID |
75783
|
| 著者 |
Ohtsu A, Arai S, Sawada T, Kato M, Maeno Y, Miyazawa Y, Fujizuka Y, Sekine Y, Koike H, Matsui H, Suzuki K.
|
| タイトル |
Fibroblast growth factor receptor inhibitor erdafitinib promotes Mcl-1 degradation and synergistically induces apoptosis with Bcl-xL/Bcl-2 inhibitor in urothelial cancer cells.
|
| ジャーナル |
Biochem Biophys Res Commun
|
| Abstract |
Metastatic urothelial cancer is a lethal disease. Although recent advances in immunotherapies and targeted therapy against fibroblast growth factor receptor (FGFR)2/3 mutation (erdafitinib) have improved patient survival, there is still a critical need for novel therapeutic strategies for patients who do not benefit from these treatments. Evasion of apoptosis through amplifying anti-apoptotic Bcl-2 family proteins (Mcl-1, Bcl-xL, Bcl-2) is one mechanism responsible for treatment resistance in urothelial cancers, suggesting that targeting anti-apoptotic proteins may be a possible therapeutic strategy for urothelial cancers. Here, we showed that erdafitinib increased Mcl-1 degradation mainly through previously unknown mechanisms and synergized with a BH3 mimetic drug targeting Bcl-xL/Bcl-2 to induce apoptosis in FGFR wild-type urothelial cancer cells. Strikingly, clinical sequencing data showed amplification of MCL1 or BCL2L1 (encoding Bcl-xL) in subsets of FGFR mutation-negative bladder cancer tissues. In conclusion, these findings suggest that exploiting apoptosis pathways may be a promising treatment strategy for patients with FGFR wild-type metastatic urothelial cancer with Mcl-1 or Bcl-xL overexpression.
|
| 巻・号 |
628
|
| ページ |
76-83
|
| 公開日 |
2022-11-5
|
| DOI |
10.1016/j.bbrc.2022.08.083
|
| PII |
S0006-291X(22)01222-0
|
| PMID |
36084554
|
| MeSH |
Antineoplastic Agents* / pharmacology
Apoptosis / drug effects
Apoptosis Regulatory Proteins / metabolism
Carcinoma, Transitional Cell* / drug therapy
Carcinoma, Transitional Cell* / metabolism
Cell Line, Tumor
Humans
Myeloid Cell Leukemia Sequence 1 Protein* / drug effects
Myeloid Cell Leukemia Sequence 1 Protein* / metabolism
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-bcl-2 / drug effects
Proto-Oncogene Proteins c-bcl-2 / metabolism
Pyrazoles / pharmacology
Quinoxalines / pharmacology
Receptors, Fibroblast Growth Factor / antagonists & inhibitors
bcl-X Protein / drug effects
bcl-X Protein / metabolism
|
| IF |
2.985
|
| リソース情報 |
| ヒト・動物細胞 |
JMSU1(RCB2227) |
