Abstract 2363: PRMT5 as a target in CRC interception: Synthetic lethal dependency identified in APC-LOF preclinical models of FAP disease

Abstract Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths in the world and loss of the Adenomatous Polyposis Coli (APC) gene represents the disease-initiating event in the majority of CRC cases. Strategies for targeting APC-loss of function (APC-LOF) may provide an opportunity to intercept tumorigenesis in high-risk CRC patients, such as those with Familial Adenomatous Polyposis (FAP). To discover targets for therapeutic intervention in APC-LOF-driven disease, we conducted a high-throughput screen in isogenic APC knockout (APCKO) colorectal organoids of >6000 compounds with known clinical relevance. From this screen, we uncovered a novel synthetic lethal dependency of APC-LOF on protein arginine methyltransferase 5 (PRMT5). JNJ-64619178 (JNJ-9178), a potent clinical PRMT5 inhibitor, demonstrated an >800-fold window in growth inhibition of engineered APCKO organoids compared to wild-type (WT). Pharmacodynamic assessments showed a dose-dependent decrease in SmD3, an established biomarker for PRMT5 target engagement, with JNJ-9178 treatment, while no decrease was observed with a weakly active compound, providing evidence that the antiproliferative activity observed in the APCKO organoids is a direct consequence of on-target PRMT5 inhibition. We further validated this PRMT5/APC dependency by testing other S-adenosylmethionine (SAM)-competitive PRMT5 inhibitors which show a similar trend in selectively inhibiting growth of the APCKO organoids vs WT. Furthermore, we assessed the impact of JNJ-9178 on colon polyp burden in the Apcmin/+-DSS mouse model, an in vivo model of FAP, where we started treatment either before (early interception) or after (late interception) significant polyp burden had been established. A 72% and 66% reduction in polyp burden was observed, respectively, compared to vehicle-treated mice after 3 weeks of dosing (BID). Taken together, these findings showcase the impact of PRMT5 inhibition in both human and mouse models of FAP disease. Orally bioavailable PRMT5 inhibitors, including JNJ-9178, present challenges as therapeutics for CRC interception due to on-target cytopenias observed with systemic exposure. To address these dose-limiting toxicities, we have developed a GI-restricted approach and discovered new compounds that only inhibit PRMT5 activity locally in the intestinal tract. This strategy is detailed in a second abstract. Citation Format: Dana S. Gaffney, Jan Willem Thuring, Fabian Hulpia, Eileen Vesely, Edward Retzbach, Zienab Etwebi, Zhengyu Jiang, Albi Francis, Bethany Mattson, Victoria Wong, Mariana Silva, Gerben ten Hag, Rene Overmeer, Carla Verissimo, Sylvia F. Boj, Johan Nicolai, Mark Hixon, Gerry Chu, Andrea DiSandro, Kathleen Clancy, Alexandra Liddane, Kurtis Bachman, David Pocalyko. PRMT5 as a target in CRC interception: Synthetic lethal dependency identified in APC-LOF preclinical models of FAP disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2363.