Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation

Publication date: 12 August 2019Source: Cancer Cell, Volume 36, Issue 2Author(s): Jia Yi Fong, Luca Pignata, Pierre-Alexis Goy, Kimihito Cojin Kawabata, Stanley Chun-Wei Lee, Cheryl M. Koh, Daniele Musiani, Enrico Massignani, Andriana G. Kotini, Alex Penson, Cheng Mun Wun, Yudao Shen, Megan Schwarz, Diana HP. Low, Alexander Rialdi, Michelle Ki, Heike Wollmann, Slim Mzoughi, Florence Gay, Christine ThompsonSummaryCancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research