Friday, May 9, 2025
5/9/2025
The Role of EP300 Mutations in Bladder Cancer Pathogenesis and Drug Response - PROJECT SUMMARY/ABSTRACT The management of metastatic bladder and upper tract urothelial cancer has been transformed over the past five years with the FDA approval of anti-PD-1/PD-L1 antibodies, antibody-drug conjugates targeting Nectin-4 and Trop-2, and the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib. Despite these clinical advances, urothelial cancer remains fatal for most patients with metastatic disease. Nearly all urothelial cancers harbor one or more mutations in chromatin modifying genes, with mutations in KDM6A, KMT2D, ARID1A, CREBBP, and EP300 being the most common. The role of mutations in these genes in urothelial cancer pathogenesis remains poorly understood, as does their impact on systemic therapy response. In preliminary studies, we find that EP300 gene knockout or loss-of-function mutation results in IL-6-JAK1-mediated STAT3 activation and resistance to erdafitinib. Based on these findings, we hypothesize that EP300 loss-of-function mutations are a mechanism of erdafitinib resistance in patients with urothelial cancer and that co-targeting IL-6-JAK1-STAT3 signaling could delay or overcome resistance to FGFR inhibitors. We will pursue three aims to investigate the phenotypic consequences of EP300 loss-of-function mutations and their role in mediating resistance to erdafitinib in patients with urothelial cancer. These aims will utilize unique resources assembled by our investigative team, including: 1) a large prospective cohort of genomically profiled urothelial cancers for which we are collecting detailed patient demographic and treatment response data, and 2) a large biobank of patient-derived organoid models of urothelial cancer. In Aim 1, we will study the role of EP300 loss-of-function mutations in mediating kinase inhibitor resistance using a large panel of patient-derived models, including FGFR3 mutant and wildtype models. We will also identify mechanism(s) of p300-independent STAT3 activation and the impact of p300- dependent and independent STAT3 activation on FGFR3 dependence. In Aim 2, we will identify genomic alterations associated with intrinsic resistance to FGFR3 inhibition using pre-treatment tumors collected from patients with urothelial cancer, with an initial focus on EP300 co-mutation as a basis for intrinsic resistance to erdafitinib. Finally, in Aim 3, we will identify mechanisms of acquired erdafitinib resistance using paired pre- and disease progression tumor and cell-free DNA samples and employ patient-derived models to test combinatorial strategies designed to overcome or delay erdafitinib resistance. The long-term translational objective of the studies proposed is to define the mechanism(s) through which EP300 mutations promote urothelial cancer pathogenesis and the impact of EP300 mutation on systemic therapy response, with the goal of using the resulting insights to develop mechanistically based combination strategies designed to prevent or delay FGFR3 inhibitor resistance. As EP300 mutations have been identified in other cancer types, the studies outlined in this proposal will also provide insights into the functional and clinical significance of EP300 mutations in cancer more broadly.
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