Splicing factor mutations increased protein arginine methyltransferase (PRMT) inhibitor sensitivity.

  • Major Finding: Splicing factor mutations increased protein arginine methyltransferase (PRMT) inhibitor sensitivity.

  • Concept: Combined treatment with inhibitors of PRMT5 and pan-type I PRMTs caused synergistic effects.

  • Impact: It may be worthwhile to screen patients in PRMT-inhibitor trials for splicing-factor mutations.

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RNA splicing factor (SF) mutations are common in leukemias and increase susceptibility to perturbations in splicing, spurring attempts to develop treatments that inhibit the spliceosome. Fong and colleagues developed a list of druggable target proteins likely to interact with the spliceosome, then performed a drug screen using a mouse cell line modeling human acute myeloid leukemia with a mutation in spliceosome component SRSF2. The screen identified several drugs that were more lethal to Srsf2-mutant cells than to wild-type Srsf2 (Srsf2WT) controls, including inhibitors of components of the extended splicing network; specifically, protein arginine methyltransferase (PRMT) inhibitors emerged as being preferentially lethal to Srsf2-mutant AML cells, which had tenfold higher sensitivity to a selective PRMT5 inhibitor and a pan-type I PRMT inhibitor. Treatment with a PRMT5 inhibitor led to increased survival in mice with Srsf2-mutant tumors but not in mice with Srsf2WT tumors, and spleens from mice treated with the drug exhibited reduced levels of symmetrical dimethylarginine. Likewise, mice with Srsf2-mutant but not Srsf2WT leukemias exhibited delayed disease progression when treated with a pan-type I PRMT inhibitor. Experiments using mouse leukemia cell lines, human leukemia cell lines, induced pluripotent stem cells differentiated into hematopoietic progenitor cells, and patient-derived xenograft mouse models all pointed to synergy between drugs targeting different aspects of splicing catalysis, and this effect was increased in the presence of mutations in SFs; experiments in human leukemia cell lines revealed that the synergistic drug effects also extended to changes in alternative splicing. PRMT5 and type I PRMTs methylated distinct groups of proteins, and genes involved in mitosis and the cell cycle were upregulated in both SRSF2WT and SRSF2-mutant cells treated with inhibitors of PRMT5, pan-type I PRMT inhibitors, or a combination of the two. Further, there was a decrease in cells in G1 and S phase and an increase in an apoptotic sub-G1 population of cells. These results suggest that mutations in splicing factors should be considered in trials of PRMT5 and type I PRMT inhibitors.

Fong JY, Pignata L, Goy P, Kawabata KC, Lee SC, Koh CM, et al. Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation. Cancer Cell 2019;36:194–209.E9.

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