Fibroblast growth factor receptor inhibitor erdafitinib promotes Mcl-1 degradation and synergistically induces apoptosis with Bcl-xL/Bcl-2 inhibitor in urothelial cancer cells

Metastatic urothelial cancer is a lethal disease. Although recent advances in immunotherapies and tar-geted 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 pre-viously 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 ampli-fication of MCL1 or BCL2L1 (encoding Bcl-xL) in subsets of FGFR mutation-negative bladder cancer tis-sues. 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.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

Metastatic urothelial cancer is a lethal disease, and novel therapeutic strategies are needed for patients who do not benefit from current treatments. This study found that targeting anti-apoptotic proteins can induce apoptosis in urothelial cancer cells and may be a promising treatment strategy for FGFR wild-type metastatic urothelial cancer patients.