PT - JOURNAL ARTICLE AU - Young H. Lee AU - Molly M. Lee AU - Dinuka M. De Silva AU - Arpita Roy AU - Cara Wright AU - Tiffany Wong AU - Rene Costello AU - Oluwole Olaku AU - Robert L. Grubb III AU - Piyush K. Agarwal AU - Andrea B. Apolo AU - Donald P. Bottaro TI - Autocrine Signaling by Receptor Tyrosine Kinases in Urothelial Carcinoma of the Bladder AID - 10.1101/2020.10.15.341206 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.10.15.341206 4099 - http://biorxiv.org/content/early/2020/10/15/2020.10.15.341206.short 4100 - http://biorxiv.org/content/early/2020/10/15/2020.10.15.341206.full AB - Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes.Competing Interest StatementD Bottaro is an inventor on US Government held patents: US 10,035,833, 9,550,818 and related international WO/2013/163606; US 8,617,831, 8,569,360 and related international WO/2009/124024, 124013; US 8,304,199, 7,964,365 and related international WO/2007/056523; and US 7,871,981 and related international WO/2001/028577 for inventions related to MET detection and inhibition, VEGFR inhibition, methods to detect and diagnose cancer, and methods to inhibit cell motility and tumor metastasis. No other authors have competing interests to disclose.TKtyrosine kinaseRTKreceptorTKctRTKRTKcabozantinib-targetedTKITK inhibitorBCabladder cancerMIBCmuscle-invasive baldder cancerOSoverall survivalPFSprogression-free survivalTCGAThe Cancer Genome AtlasEMTepithelial-to-mesenchymal transitionTAtranscriptional activator