UNDERSTANDING THE REGULATORY CONTEXT OF FGFR3 ALTERED BLADDER TUMORS, KEY TRANSCRIPTION FACTORS AS NEW POSSIBLE THERAPEUTIC TARGETS

ZAMBRANO M ; SCIACCA M ; MORENO-VEGA AI ; LANGLE YV ; BERNARDPIERROT I ; EIJAN ANA MARIA ; LODILLINSKY C

MODALIDAD VIRTUAL

Congreso; Reunion Conjunta de Sociedades de Biociencias SAIC SAI SAFE; 2020

SAIC SAI SAFE

Currently bioinformatic studies aim to understand the underlying mechanisms inbladder cancer (BC). FGFR3 is the most common alteration in BC, its oncogenicpotential has been demonstrated and target therapies have been developed.However, like other target therapies it is expected that patients developresistance. The identification of additional therapeutic options to use concomitantor sequentially with these ones could help in this matter. In this context, ourobjective is to identify transcription factors (TFs) that could be new potentialtargets in FGFR3-altered (FGFR3*) bladder tumors. Using a BC gene regulatorynetwork, publicly available data and our transcriptomic data we obtained theactivation profile of the TFs activated in an FGFR3* context, we identified FOXM1and p63 as essential and highly active TFs. We generated a p63 target genesignature from MGHU3 cells by ChIP-seq integrated with the siTP63 RNA-seqexpression profiling. Consistently with our previous experimental results, geneontology enrichment analysis revealed that p63 positively mediates cellularprocesses such as migration, invasion, proliferation, and represses cell death.We demonstrated that altered FGFR3 regulates p63 at mRNA and protein levelby using a panFGFR inhibitor (PD173075) in human FGFR3* BC cell lines.Analysis of mRNA levels in human bladder tumors showed a correlation betweenFGFR3 and TP63 expression in both Non muscle invasive BC (r=0.57,p=6.59e10) and muscle invasive BC (r=0.50,p=1.34e-07) FGFR3*. We also probed thatinhibition of FGFR3 blunted the carcinogenic program carried out by p63diminishing migration and proliferation at equivalent levels than specific silencingof p63 in BC cells. In summary, we identified p63 a new possible target in FGFR3*BC, where we demonstrated the FGFR3 regulation over the protumoral TF p63.Additionally, we validated the gene regulatory network through experiments andreinforced our previous results with bioinformatics.