Abstract B020: Development of novel Src-targeting strategies to block bladder cancer invasive progression

Abstract

Abstract Background: Treatment of muscle-invasive bladder cancer remains challenging and, BCG, one of the few treatments that prevents progression of high-risk non-muscle invasive tumors to invasive metastatic disease, is difficult to obtain. Thus, development of new treatment approaches to block progression to muscle invasive disease is essential. We find that TRIM29 (tripartite motif containing 29, also known as ATDC), drives bladder cancer invasive progression through modulation of focal adhesions containing FAK and c-Src (Src). Despite this, literature has reported conflicting effects of Src knockdown and Src kinase inhibition on migration, perhaps due to separable pro- and anti-invasive functions of Src in bladder cancer. Hypothesis: Src drives bladder cancer invasive progression specifically through its tyrosine kinase activity within focal adhesions. Methods: We used 2D live cell migration assays and 3D spheroid invasion assays to test dasatinib, highly specific, novel conformation inhibitors of Src, a novel Src PROTAC, and siRNA against Src on bladder cancer migration and invasion. Results: Dasatinib and our novel conformation-specific inhibitors inhibited Src kinase activity and both siRNA and the novel PROTAC reduced total Src expression in vitro. Neither dasatinib, conformation inhibitors, siRNA, nor the PROTAC impacted bladder cancer cell viability in UM-UC5, UM-UC9 or UM-UC14 cell lines. Interestingly, we found that inhibiting Src’s kinase activity with either dasatinib or conformation-specific inhibitors abrogated bladder cancer migration. Conclusion: These results point to the selective importance of Src in regulating bladder cancer migration and invasion. They also suggest that novel Src targeting agents have potential clinical utility in the prevention of bladder cancer invasive progression. Citation Format: Nicole A. Jerome, Yin Wang, Marian L. Henderson, Luke Broses, Kathleen C. Day, Mark L. Day, Matthew B. Soellner, Phillip L. Palmbos. Development of novel Src-targeting strategies to block bladder cancer invasive progression [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B020.