Abstract LB-317: Anti-invasive effects of saracatinib in preclinical models of luminal bladder cancer

Abstract

Abstract Bladder cancers (BC) form biologically and clinically distinct luminal and basal subtypes. In both subtypes, identifying treatments to prevent progression from non-muscle invasive to muscle invasive disease is a major clinical priority. Anti-invasive agents, such as the SRC and SRC-Family Kinase inhibitor, saracatinib, may benefit high risk non-muscle invasive BC patients. We hypothesized that SRC inhibition limits invasion in bladder tumor models. We examined SRC mRNA expression in the luminal and basal subtypes of BC using publicly available The Cancer Genome Atlas (TCGA) data. Using RNA-Seq expression data, we classified 30 human BC cell lines as luminal or basal and compared SRC expression between the subtypes. We then studied the effect of saracatinib in luminal and basal BC models. Proliferation was measured by MTT assay and invasion was measured using transwell assays. Transwells were either uncoated (modeling migration), matrigel coated (modeling basement membrane invasion) or collagen-1 coated (modeling muscle wall invasion). Luminal TCGA bladder tumors showed significantly enrichments in SRC mRNA expression (p<0.001). SRC expression was significantly higher in luminal than basal cell lines (p<0.05). Saracatinib had limited anti-proliferative activity in both luminal and basal models. All luminal models showed significantly decreased migration and collagen 1 invasion (p<0.05). Of the subset of luminal cell lines that invade matrigel, two thirds had significantly decreased invasion (p<0.05). Only one basal cell line exhibited significantly decreased invasion or migration (p<0.05). Invasion and migration in other basal models were not significantly altered or, in several case, were significantly increased (p<0.05), by saracatinib. Enrichment of SRC expression in luminal tumors and significant reductions in luminal cell line invasion after saracatinib treatment suggest SRC promotes invasion in luminal BC. The increase in basal cell line invasion, observed in a subset of these models, emphasizes the importance of considering subtype in studying the biology of BC. Though further validation in 3D culture and animal models is necessary, these results suggest saracatinib, and other SRC-Family Kinase inhibitors, could serve as effective anti-progression agents in luminal BC. Citation Format: Bryan Wehrenberg, David Neal, Andrea Ochoa, Woonyoung Choi, David McConkey. Anti-invasive effects of saracatinib in preclinical models of luminal bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-317.