Bladder cancer (BCa) is the second most common urologic tumor entity in men after prostate cancer. The different molecular classes of BCa are very heterogeneous, requiring distinct targeted therapies. In 2019, the FGFR3 inhibitor Erdafitinib was approved by the FDA for BCa patients harboring FGFR3 genetic alterations (40% of the Luminal Papillary (LumP) subgroup of muscle-invasive BCa (MIBC)). However, tumor progression has been observed in some patients after a few months of therapy due to the rapid development of acquired resistance.

Using BCa cell culture model, we have shown, that pre-adipocytes of the microenvironment promote the development of Erdafitinib resistance through the secretion of NRG1 leading to the activation of the HER3 signaling pathway in BCa. Importantly, blocking the HER3 receptor using inhibitory antibodies restores the sensitivity to Erdafitinib.

However, further validation in vivo still missing, which can provide the rationale for the use of combination therapy of FGFR3- and HER3-inhibitors in FGFR3-mutated BCa in clinical setting.