Identification of New Therapeutic Targets for Renal Medullary Carcinoma via Integrated Genomic and Transcriptomic Profiling

Purpose: Renal medullary carcinoma (RMC) is a rare, aggressive kidney cancer associated with sickle cell trait, characterized by SMARCB1 loss and resistance to conventional therapies used for other renal cell carcinomas (RCC). This study aimed to perform comprehensive histopathologic, genomic, and transcriptomic profiling of RMC tissues to identify novel therapeutic targets. Experimental Design: We conducted whole exome sequencing (WES) and bulk RNA-sequencing (RNA-seq) on 15 RMC samples, using cellular deconvolution to characterize the tumor microenvironment (TME) and identify potential therapeutic targets. Gene expression profiles and TME composition were compared with other RCCs, internally available cohorts of other solid and neuroendocrine tumors, and the Cancer Genome Atlas. Immunohistochemistry (IHC) confirmed TROP2 expression, and four heavily pretreated patients with high TROP2 expression were prospectively treated with sacituzumab govitecan. Results: There was significant upregulation of TROP2, EPCAM, CLDN6, and CDH6, positioning them as potential therapeutic targets. Pathway analyses indicated upregulation of the Hippo, pathway and distinct TME features, including high levels of fibroblasts and neutrophils. Among the four patients treated with sacituzumab govitecan, one achieved a partial response with symptom improvement, while two achieved stable disease. The median progression-free survival was 2.9 months. Conclusions: This study provides the largest molecular characterization of RMC to date, highlighting TROP2 and other cell surface markers as promising therapeutic targets. Sacituzumab govitecan may offer clinical benefit for RMC patients with high TROP2 expression. Further investigation in prospective clinical trials is warranted to confirm the efficacy of TROP2-targeted therapies and explore additional targets like EPCAM and CLDN6.