Identification of a novel dependency between PRMT5 and APC-LOF in preclinical models of FAP disease

Abstract

Strategies for targeting adenomatous polyposis coli ( 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). Here, we uncovered a novel synthetic lethal dependency of APC -LOF on protein arginine methyltransferase (PRMT5). JNJ-64619178 (JNJ-9178), a potent clinical (PRMT5) inhibitor, demonstrated >800-fold more growth inhibition of engineered APC KO organoids compared to wild-type isogenic congeners. We further confirmed this PRMT5/APC dependency by testing other PRMT5 inhibitors with various chemotypes and mechanisms of action. Notably, less antiproliferative activity was observed with methylthioadenosine (MTA)-cooperative PRMT5 inhibitors, MRTX1719 and TNG462. Furthermore, we assessed the impact of JNJ-9178 on colon adenoma burden in the Apc min+ -DSS mouse model, where we started treatment either before (early interception) or after (late interception) measurable adenoma burden had been established. A 72% and 66% reduction in adenoma burden was observed, respectively, compared to vehicle-treated mice, suggesting that PRMT5 inhibition both suppresses polyp growth and reduces existing polyp burden. The data we present here suggests that PRMT5 inhibition in the colon offers a strategy to intercept tumorigenesis in patients at a high risk of developing APC -LOF-driven CRC.