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Learn MoreAbstract Background: Histone deacetylase (HDAC) inhibition has shown some efficacy in urothelial carcinoma (UC); the genomic basis for clinical response is not known. Methods: In two separate phase I clinical trials testing HDAC inhibitors in advanced solid tumors, we identified one patient with advanced UC who had a complete response (CR) to belinostat and one with advanced UC who had a partial response (PR) to panobinostat. The archived tumor of the responders was genomically characterized and studied in comparison to others with UC, in the context of their response to HDAC inhibition on trial. UC cell lines treated with panobinostat were studied to elucidate the mechanisms of benefit. Results: The two patients who responded to HDAC inhibition had ARID1A and FANCD2 mutations. The patient who had a CR to HDAC inhibition had the highest tumor mutational burden of all tumors. Corroborating the basis of sensitivity, transcriptional profiling of platinum resistant ARID1A mutated HT1197 cells treated with panobinostat revealed downregulation of cyto-proliferative and DNA repair gene sets and upregulation of inflammatory gene sets. Conclusions: Clinical efficacy of HDAC inhibition in UC may be dependent on overlapping SWI/SNF pathway mutations and DNA repair defects. Tumor mutational burden may predict the depth and duration of benefit. SOURCE: Sumati Gupta (sumati.gupta@hci.utah.edu) - Gupta Lab Huntsman Cancer Institute
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