Muscle-invasive bladder cancers (MIBC) and upper urinary tract urothelial carcinomas (UTUC) represent a group of tumors that are highly heterogeneous at both the morphological and molecular levels. Despite the use of chemotherapy, immunotherapy, or fibroblast growth factor receptor (FGFR) inhibitors, their prognosis remains poor: the five-year overall survival of MIBC ranges between 50 and 60%, and falls below 10% in metastatic disease. No standard-of-care treatment exists for squamous cell carcinomas (SCC), a rarer form than urothelial carcinomas (UC). In this context, the development of preclinical models that faithfully recapitulate patient tumors represents an essential lever for identifying new therapies.
The authors established a bank of patient-derived xenografts (PDX), obtained by subcutaneous grafting of fresh tumors into immunodeficient mice. Matched tumors of origin and PDX were compared at the histopathological, transcriptomic (DNA microarrays), and genomic (targeted next-generation sequencing) levels. Several models were then treated with chemotherapy (cisplatin/gemcitabine) or with targeted therapies directed against FGFR and EGFR. In total, 31 PDX were established from 1 non-invasive tumor, 25 MIBC, and 5 upper tract tumors, including 28 UC and 3 SCC.
The integrated analysis recovered the three consensus molecular subtypes — basal/squamous (Ba/Sq), luminal papillary, and luminal unstable — as well as models harboring FGFR3 mutations. Histological and genomic concordance between matched tumors and PDX was high, but the transcriptomic profile proved less stable: in five cases, a Ba/Sq tumor gave rise to a luminal papillary PDX, suggesting an intrinsic cellular plasticity, possibly linked to differences in stroma between the immunodeficient mouse and the human tumor. Among ten models treated with chemotherapy, no association between subtype and response was observed. Among three Ba/Sq models treated with anti-EGFR therapy, two were sensitive, whereas the sarcomatoid variant model — characterized by low EGFR activity — was resistant. Finally, combined inhibition of FGFR and EGFR proved more effective than FGFR3 inhibition alone in FGFR3-mutated PDX, with anti-FGFR alone inducing compensatory overexpression of EGFR, ERBB2, and ERBB3.
These models reproduce the molecular heterogeneity of MIBC and UTUC, including actionable mutations. The pharmacological characterization indicates that the upper tract and the bladder, whether UC or SCC, share therapeutic responses when they exhibit similar molecular features: anti-FGFR therapy for FGFR3-mutated tumors, and anti-EGFR therapy for basal tumors. This work supports the value of combined FGFR/EGFR inhibition in FGFR3-mutated tumors.