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 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.

Apoptosis; BH3 mimetic; Bcl-xL; Bladder cancer; FGFR; Mcl-1.