Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation

Cancer-associated mutations in RNA splicing factors commonly occur in myeloid and lymphoid leukemias as well as a variety of solid tumors and confer dependence on wild-type (WT) splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here we identify that inhibiting symmetric (SDMA) or asymmetric dimethyl arginine methylation (ADMA), mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs) respectively, reduces splicing fidelity and results in strong preferential killing of spliceosomal mutant leukemias over WT counterparts. Consistent with this, proteomic analyses identified RNA binding proteins and splicing factors as the most enriched PRMT5 and/or PRMT Type I substrates in leukemia. Accordingly, combined PRMT5/type I PRMT inhibition resulted in synergistic cell killing and pronounced effects on splicing compared with inhibiting either enzymatic activity alone. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.