ABSTRACT
Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies.
Subject(s)
Carcinoma, Transitional Cell/pathology , Kidney Neoplasms/pathology , Receptor, Fibroblast Growth Factor, Type 3/metabolism , T-Lymphocytes/immunology , Ureteral Neoplasms/pathology , Aged , Aged, 80 and over , Carcinoma, Transitional Cell/genetics , Carcinoma, Transitional Cell/immunology , DNA Mutational Analysis , Down-Regulation , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Kidney Neoplasms/genetics , Kidney Neoplasms/immunology , Male , Microsatellite Instability , Middle Aged , Mutation , Receptor, Fibroblast Growth Factor, Type 3/genetics , Sequence Analysis, RNA , Signal Transduction/genetics , Tumor Microenvironment/immunology , Ureteral Neoplasms/genetics , Ureteral Neoplasms/immunology , Urothelium/pathology , Exome SequencingABSTRACT
Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study, we show that ERG overexpression in in vitro and in vivo models of CRPC is associated with decreased sensitivity to taxanes. ERG affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of docetaxel or cabazitaxel with tubulin. Finally, analysis of a cohort of 34 men with metastatic CRPC treated with docetaxel chemotherapy reveals that ERG-overexpressing prostate cancers have twice the chance of docetaxel resistance than ERG-negative cancers. Our data suggest that ERG plays a role beyond regulating gene expression and functions outside the nucleus to cooperate with tubulin towards taxane insensitivity. Determining ERG rearrangement status may aid in patient selection for docetaxel or cabazitaxel therapy and/or influence co-targeting approaches.
