STAG2 expression imparts distinct therapeutic vulnerabilities in muscle-invasive bladder cancer cells.

Abstract

Expression of stromal antigen 2 (STAG2), a member of the cohesin complex, is associated with aggressive tumor characteristics and worse clinical outcomes in muscle invasive bladder cancer (MIBC) patients. The mechanism by which STAG2 acts in a pro-oncogenic manner in bladder cancer remains unknown. Due to this elusive role of STAG2, targetable vulnerabilities based on STAG2 expression have not yet been identified. In the current study, we sought to uncover therapeutic vulnerabilities of muscle invasive bladder cancer cells based on the expression of STAG2. Using CRISPR-Cas9, we generated isogenic STAG2 wild-type (WT) and knock out (KO) cell lines and treated each cell line with a panel of 312 anti-cancer compounds. We identified 100 total drug hits and found that STAG2 KO sensitized cells to treatment with PLK1 inhibitor rigosertib, whereas STAG2 KO protected cells from treatment with MEK inhibitor TAK-733 and PI3K inhibitor PI-103. After querying drug sensitivity data of over 4500 drugs in 24 bladder cancer cell lines from the DepMap database, we found that cells with less STAG2 mRNA expression are more sensitive to ATR and CHK inhibition. In dose-response studies, STAG2 KO cells are more sensitive to the ATR inhibitor berzosertib, whereas STAG2 WT cells are more sensitive to PI3K inhibitor PI-103. These results, in combination with RNA-seq analysis of STAG2-regulated genes, suggest a novel role of STAG2 in regulating PI3K signaling in bladder cancer cells. Finally, synergy experiments revealed that berzosertib exhibits significant synergistic cytotoxicity in combination with cisplatin against MIBC cells. Altogether, our study presents evidence that berzosertib, PI-103, and the combination of berzosertib with cisplatin may be novel opportunities to investigate as precision medicine approaches for MIBC patients based on STAG2 tumor expression.