RRC ID 75783
Author Ohtsu A, Arai S, Sawada T, Kato M, Maeno Y, Miyazawa Y, Fujizuka Y, Sekine Y, Koike H, Matsui H, Suzuki K.
Title Fibroblast growth factor receptor inhibitor erdafitinib promotes Mcl-1 degradation and synergistically induces apoptosis with Bcl-xL/Bcl-2 inhibitor in urothelial cancer cells.
Journal 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.
Volume 628
Pages 76-83
Published 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
Human and Animal Cells JMSU1(RCB2227)