Abstract
BackgroundMuscle-invasive bladder cancer (MIBC) is an aggressive neoplasm with poor prognosis, lacking effective therapeutic targets. Oncogenic dependency on members of the TAM tyrosine kinase receptor family (TYRO3, AXL, MERTK) has been reported in several cancer types, but their role in bladder cancer has never been explored.MethodsTAM receptor expression was evaluated in two series of human bladder tumours by gene expression (TCGA and CIT series), immunohistochemistry and western blotting analyses (CIT series). The role of the different TAM receptors was assessed by loss-of-function experiments and pharmaceutical inhibition in vitro and in vivo.ResultsWe reported a significantly higher expression of TYRO3, but not AXL or MERTK, in both non-MIBCs and MIBCs, compared to normal urothelium. Loss-of-function experiments identified a TYRO3-dependency of bladder carcinoma-derived cells both in vitro and in a mouse xenograft model, whereas AXL and MERTK depletion had only a minor impact on cell viability. Accordingly, TYRO3-dependent bladder tumour cells were sensitive to pharmacological treatment with two pan-TAM inhibitors. Finally, growth inhibition upon TYRO3 depletion relies on cell cycle inhibition and apoptosis associated with induction of tumour-suppressive signals.ConclusionsOur results provide a preclinical proof of concept for TYRO3 as a potential therapeutic target in bladder cancer.
Highlights
Muscle-invasive bladder cancer (MIBC) is an aggressive neoplasm with poor prognosis, lacking effective therapeutic targets
TYRO3 is highly expressed in bladder carcinomas We first investigated the role of TAM receptors in human bladder carcinoma, by analysing, using RT-qPCR, the levels of expression of AXL, MERTK, TYRO3 and GAS6 in our previously described CIT cohort of 169 bladder tumours encompassing 87 NMIBCs and 82 MIBCs.[5,11]
Expression levels for the three receptors and their ligand were heterogeneous in tumours, with only TYRO3 significantly elevated in NMIBCs and MIBCs relative to normal samples
Summary
Muscle-invasive bladder cancer (MIBC) is an aggressive neoplasm with poor prognosis, lacking effective therapeutic targets. Oncogenic dependency on members of the TAM tyrosine kinase receptor family (TYRO3, AXL, MERTK) has been reported in several cancer types, but their role in bladder cancer has never been explored. Loss-of-function experiments identified a TYRO3-dependency of bladder carcinoma-derived cells both in vitro and in a mouse xenograft model, whereas AXL and MERTK depletion had only a minor impact on cell viability. TYRO3-dependent bladder tumour cells were sensitive to pharmacological treatment with two pan-TAM inhibitors. New effective therapies targeting both MIBCs and non-muscle-invasive tumours (NMIBCs), which often recur, are required. Efforts to decipher the molecular mechanisms involved in bladder carcinogenesis have led to the identification of a number of possible new treatment targets, such as mTOR in patients with TSC1 mutations, epidermal growth factor receptor 2 (HER2)/ERBB2 in HER2positive tumours, EGFR in basal-like tumours, and fibroblast growth factor receptors, in patients harbouring mutations or gene fusions of FGFR3.3–5
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