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|Ref Type||Journal Article|
|Authors||Fong JY, Pignata L, Goy PA, Kawabata KC, Lee SC, Koh CM, Musiani D, Massignani E, Kotini AG, Penson A, Wun CM, Shen Y, Schwarz M, Low DH, Rialdi A, Ki M, Wollmann H, Mzoughi S, Gay F, Thompson C, Hart T, Barbash O, Luciani GM, Szewczyk MM, Wouters BJ, Delwel R, Papapetrou EP, Barsyte-Lovejoy D, Arrowsmith CH, Minden MD, Jin J, Melnick A, Bonaldi T, Abdel-Wahab O, Guccione E|
|Title||Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation.|
|Date||2019 08 12|
|Abstract Text||Cancer-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.|
|Molecular Profile||Treatment Approach|
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|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
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|KMT2A - MLLT3||acute myeloid leukemia||sensitive||E7107 + MS023||Preclinical - Cell culture||Actionable||In a preclinical study, MS023 and E7107 synergistically inhibited survival of murine KMT2A-MLLT3 (reported as MLL-AF9)-driven acute myeloid leukemia cells in culture, regardless of SRSF2 mutation status (PMID: 31408619).||31408619|
|KMT2A - MLLT3||acute myeloid leukemia||sensitive||E7107 + GSK3203591||Preclinical - Cell culture||Actionable||In a preclinical study, E7107 and GSK3203591 synergistically inhibited survival of murine KMT2A-MLLT3 (reported as MLL-AF9)-driven acute myeloid leukemia cells in culture, regardless of SRSF2 mutation status (PMID: 31408619).||31408619|
|KMT2A - MLLT3||acute myeloid leukemia||sensitive||GSK3203591 + MS023||Preclinical - Cell culture||Actionable||In a preclinical study, MS023 and GSK3203591 synergistically inhibited survival of murine KMT2A-MLLT3 (reported as MLL-AF9)-driven acute myeloid leukemia (AML) cells and human AML cell lines harboring KMT2A-MLLT3 in culture (PMID: 31408619).||31408619|