Abstract 3991: Ts65Dn Down syndrome mice reveal a potential therapeutic vulnerability in a BBN bladder cancer model and subset of bladder cancer cell lines

Abstract

Abstract Trisomy 21, Down Syndrome, results in a constellation of symptoms including increased risk for leukemia. In contrast, mounting evidence indicates that people with Down Syndrome have lower rates of numerous solid tumors, particularly carcinogen driven cancers, even when adjusted for age. The mechanisms that dictate why this occurs are not well understood but could potentially yield actionable targets for treating or preventing cancer formation. We hypothesized Ts65Dn mice, a murine model of Down Syndrome, would be protected against BCa formation and could be evaluated as a genetic basis for the discovery of novel therapeutic targets in bladder cancer. Using the well characterized N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) chemical carcinogen bladder cancer model we initiated tumors in Ts65Dn and WT mice. After 16 weeks BBN exposure, TS65Dn mice were found to have smaller bladder tumors by weight with a trend toward lower stages as compared to WT animals. RNA-sequencing was used to assess broad genomic changes in the tumors. Reactome analysis of the RNA-sequencing data indicated pathways associated with mitosis and the cell cycle were most affected in Ts65Dn mice, including downregulation of pathways associated with Aurora Kinase B (AURKB). AURKB is a pro-tumorigenic kinase known to enhance cell survival and proliferation. Bioinformatics analysis indicates that while AURKB is broadly expressed in most tissues, it is potently upregulated in bladder cancers, offering a potential therapeutic target. Using the AURKB specific inhibitor barasertib-HQPA we evaluated drug sensitivity in a set of BCa cell lines. Cell lines associated with a basal subtype gene signature (5637, HT-1376) were largely susceptible to barasertib with IC50 values in nM concentrations, whereas other BCa cell lines (HTB-5, T24) had IC50 values nearly 1,000X higher. We next assessed histone H3 phosphorylation, a known substrate of AURKB, to validate drug efficacy. Interestingly, inhibition of histone H3 phosphorylation was noted in all cell lines at nM concentrations, indicating that while barasertib is functionally active in both sets of cells, the anti-proliferative activity is not dependent upon phosphorylation of histone H3, but rather other factors that we have yet to determine. In conclusion, we have found Ts65Dn mice have reduced tumor formation when exposed to the BCa carcinogen BBN and furthermore, have identified AURKB as a potential therapeutic target. Use of Ts65Dn mice may be a relevant model for identifying potentially undefined tumorigenic agents in multiple cancers including bladder. Citation Format: Binh Vo, Erika Abbott, Carolyn J. Vivian, Xena Moore, Ganeshkumar Rajendran, Katie Dennis, Benjamin L. Woolbright, Scott J. Weir, John A. Taylor. Ts65Dn Down syndrome mice reveal a potential therapeutic vulnerability in a BBN bladder cancer model and subset of bladder cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3991.