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KEGG's bladder cancer map shows two routes: low-grade papillary tumours driven by FGFR3 or HRAS activating the MAPK relay, and high-grade invasive tumours that lose TP53 and RB1. Erdafitinib targets the first route; antibody-drug conjugates and PD-1 antibodies now anchor treatment of the second.
The KEGG bladder cancer map (hsa05219) draws the divergent pathways of urothelial carcinoma. Low-grade, non-invasive papillary tumours arise from urothelial hyperplasia and show constitutive receptor tyrosine kinase to RAS signalling: activating mutations in FGFR3 or HRAS, or overexpression of EGFR and ERBB2, feed RAF to MEK to ERK, MYC and cyclin D1 to drive proliferation. Flat carcinoma in situ and invasive tumours instead show loss of the TP53 and RB pathways: TP53 mutation or MDM2 amplification, RB1 loss or mutation, and deletion of the CDKN2A locus (p16 and p14ARF), which together remove the G1/S checkpoint. Invasion and metastasis are promoted by loss of E-cadherin (CDH1), matrix metalloproteinases (MMP1, MMP2, MMP9), and angiogenic factors such as VEGFA and IL-8 (CXCL8), with thrombospondin-1 as the anti-angiogenic counterweight. Knowles and Hurst, Nat Rev Cancer, 2015 (doi:10.1038/nrc3817) review this two-pathway model in the light of genome sequencing, adding the very high rate of chromatin regulator mutations (KDM6A, ARID1A, KMT2D), TERT promoter mutations, and the luminal and basal expression subtypes of muscle-invasive disease.
What drugs do about it: the pan-FGFR inhibitor erdafitinib is approved for advanced urothelial carcinoma with FGFR3 alterations. For the high-grade, p53-pathway-deficient majority, the Nectin-4 antibody-drug conjugate enfortumab vedotin with pembrolizumab has replaced platinum chemotherapy as first-line treatment, PD-1 and PD-L1 antibodies (pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab) are used as maintenance and in the perioperative setting, and the HER2 antibody-drug conjugate disitamab vedotin targets ERBB2-overexpressing tumours.
Two roads to the same city. The slow road (papillary tumours) is a stuck accelerator, FGFR3 or HRAS. The fast road (invasive tumours) is brake failure, TP53 and RB1 lost. Erdafitinib fixes the accelerator on the slow road; antibody-drug conjugates and immunotherapy deal with cars that have already reached the city.
Shares MDM2, MEK1/2, The cell-cycle engine (cyclins & CDKs), CDKN2A.
Shares FGF / FGFR signalling, Epithelial-mesenchymal transition & drug efflux, p53 / RB / cell-cycle checkpoint, PD-1 / PD-L1 immune checkpoint & T-cell activation.
Shares The cell-cycle engine (cyclins & CDKs), RB1, MYC, CDK4/6.
Shares VEGF angiogenesis, RB1, CDKN2A, p53 / RB / cell-cycle checkpoint.
Shares MDM2, VEGF angiogenesis, CDKN2A, CDK4/6.
Shares Enfortumab vedotin, Durvalumab, Nivolumab, Bladder & urothelial cancer.
Shares Avelumab, Atezolizumab, Durvalumab, Nivolumab.
Shares Erdafitinib, FGF / FGFR signalling, VEGF angiogenesis, Epithelial-mesenchymal transition & drug efflux.