GSE126651
Tumor intrinsic PRMT5 inhibition through MTAP loss predicts response to the first-in-class type I PRMT inhibitor, GSK3368715
Type I Protein Arginine Methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginine (ADMA) residues on numerous protein substrates to modulate their activity. Type I PRMTs and many of their substrates have been implicated in human cancers, suggesting that inhibiting Type I PRMT activity offers a tractable approach for therapeutic intervention. The current report describes GSK3368715 (EPZ019997), a potent, reversible Type I PRMT inhibitor with anti-tumor activity against human cancer cells both in vitro and in vivo. GSK3368715 reduces ADMA on numerous substrates and concomitantly increases monomethyl (MMA) and symmetric dimethyl arginine (SDMA) levels. Inhibition of PRMT5, the major type II PRMT, attenuates this induction and produces synergistic antiproliferative effects in combination with GSK3368715 in cancer cells. PRMT5 activity is inhibited by 2-methylthioadenosine (MTA), a naturally occurring metabolite that accumulates in tumor cells deficient for the enzyme Methylthioadenosine Phosphorylase (MTAP). MTAP deletion in cancer cell lines correlates with sensitivity to GSK3368715, indicating a sufficient degree of PRMT5 inhibition from MTA accumulation to achieve a tumor cell-intrinsic combination. These data provide the rationale to explore MTAP status as a biomarker strategy for patient selection to maximize the anti-tumor activity of GSK3368715. Overall design: Paired-end sequenced RNA-seq data from 5 pancreatic cancer cell lines. HuPT4, BxPC3, Capan-2, PANC08.13 have been sequenced with 2 replicates, containing GSK3368712 (treated) and control (DMSO) samples. PANC03.27 has isogenic MTAP CRISPR knockout and parental samples with 2 replicates, each containing GSK3203591, GSK3368712 and a combination of the two (Combo) treatments.