Abstract
The JAK-STAT signalling pathway regulates cellular processes like cell division, cell death and immune regulation. Dysregulation has been identified in solid tumours and STAT3 activation is a marker for poor outcome. The aim of this study was to explore potential therapeutic strategies by targeting this pathway in bladder cancer (BC). High STAT3 expression was detected in 51.3% from 149 patient specimens with invasive bladder cancer by immunohistochemistry. Protein expression of JAK, STAT and downstream targets were confirmed in 10 cell lines. Effects of the JAK inhibitors Ruxolitinib and BSK-805, and STAT3/5 inhibitors Stattic, Nifuroxazide and SH-4-54 were analysed by cell viability assays, immunoblotting, apoptosis and cell cycle progression. Treatment with STAT3/5 but not JAK1/2 inhibitors reduced survival, levels of phosphorylated STAT3 and Cyclin-D1 and increased apoptosis. Tumour xenografts, using the chicken chorioallantoic membrane (CAM) model responded to Stattic monotherapy. Combination of Stattic with Cisplatin, Docetaxel, Gemcitabine, Paclitaxel and CDK4/6 inhibitors showed additive effects. The combination of Stattic with the oncolytic adenovirus XVir-N-31 increased viral replication and cell lysis. Our results provide evidence that inhibitors against STAT3/5 are promising as novel mono- and combination therapy in bladder cancer.
Highlights
Bladder cancer (BC) is the 10th most common cancer in the world, as of 2018 [1]
Using a STAT3 transgenic mouse model, chemical induction of bladder cancer by N-butyl-N-(4-Hydroxybutyl) nitrosamine (BBN) directly resulted in the development of invasive carcinoma from carcinoma in situ, asserting the role of STAT3 in bladder cancer progression [18]. Considering these findings, we explored targeting of the JAK1/2 and STAT3/5 proteins using specific small molecule inhibitors and combined these inhibitors with standard chemotherapy, inhibitors of cell cycle progression and oncolytic adenovirus in preclinical models of bladder cancer
We included the 4 JAK family proteins and 7 STAT family proteins and analysed the data in the The Cancer Genome Atlas (TCGA) cohort consisting of 412 bladder cancer patients to identify molecular alterations in the JAK-STAT signalling pathway related genes (Table S1) [45]
Summary
25% of patients present as muscle invasive bladder cancer (MIBC) at time of diagnosis. Metastasized BC patients face a poor outcome with median survival time of approximately 14 months and the survival rates have remained largely unchanged for the past 30 years until the emergence of immune checkpoint inhibitors (ICB). Clinical trials so far have demonstrated that only sub-cohorts of patients benefit from those treatment strategies, probably due to required molecular alterations for therapy response [6]. In 2019, the FGFR inhibitor Balversa (Erdafitinib) was approved by the FDA (Food and Drug Administration) for treatment of patients with metastatic bladder cancer harbouring molecular alterations in FGFR2/3, marking it to be the first targeted therapy to be approved in bladder cancer [7]. It is necessary to identify suitable molecular targets and predictive markers and combination therapies that broaden the spectrum of responders to treatment
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