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

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 Thompson; Timothy Hart; Olena Barbash; Genna M Luciani; Magdalena M Szewczyk; Bas J Wouters; Ruud Delwel; Eirini P Papapetrou; Dalia Barsyte-Lovejoy; Cheryl H Arrowsmith; Mark D Minden; Jian Jin; Ari Melnick; Tiziana Bonaldi; Omar Abdel-Wahab; Ernesto Guccione

doi:10.1016/j.ccell.2019.07.003

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

Cancer Cell. 2019 Aug 12;36(2):194-209.e9. doi: 10.1016/j.ccell.2019.07.003.

Authors

Jia Yi Fong¹, Luca Pignata², Pierre-Alexis Goy², Kimihito Cojin Kawabata³, Stanley Chun-Wei Lee⁴, Cheryl M Koh⁵, Daniele Musiani⁶, Enrico Massignani⁶, Andriana G Kotini⁷, Alex Penson⁴, Cheng Mun Wun⁵, Yudao Shen⁸, Megan Schwarz⁷, Diana Hp Low⁵, Alexander Rialdi⁷, Michelle Ki⁴, Heike Wollmann⁵, Slim Mzoughi⁵, Florence Gay⁵, Christine Thompson⁹, Timothy Hart⁹, Olena Barbash⁹, Genna M Luciani¹⁰, Magdalena M Szewczyk¹⁰, Bas J Wouters¹¹, Ruud Delwel¹², Eirini P Papapetrou⁷, Dalia Barsyte-Lovejoy¹⁰, Cheryl H Arrowsmith¹³, Mark D Minden¹⁴, Jian Jin⁸, Ari Melnick³, Tiziana Bonaldi⁶, Omar Abdel-Wahab¹⁵, Ernesto Guccione¹⁶

Affiliations

¹ Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore.
² Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.
³ Departments of Medicine and Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA.
⁴ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁵ Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore.
⁶ Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20146 Milan, Italy.
⁷ Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁸ Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹ Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
¹⁰ Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
¹¹ Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA; Department of Hematology, Erasmus University Medical Center, 3015 GD Rotterdam, Netherlands.
¹² Department of Hematology, Erasmus University Medical Center, 3015 GD Rotterdam, Netherlands.
¹³ Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; Ontario Cancer Institute/Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
¹⁴ Ontario Cancer Institute/Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
¹⁵ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: [email protected].
¹⁶ Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A(∗)STAR), Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore; Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacological Sciences and Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: [email protected].

Abstract

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.

Keywords: AML; Arginine methylation; MDS; MS023; PRMT1; PRMT5; SF3B1; SRSF2; Splicing factor mutations; U2AF1.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Catalysis
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Ethylenediamines / pharmacokinetics
Ethylenediamines / pharmacology*
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
K562 Cells
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism
Mice, Inbred C57BL
Mice, Transgenic
Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
Protein-Arginine N-Methyltransferases / genetics
Protein-Arginine N-Methyltransferases / metabolism
Pyrroles / pharmacokinetics
Pyrroles / pharmacology*
RNA Splicing / drug effects*
RNA, Neoplasm / genetics
RNA, Neoplasm / metabolism*
Repressor Proteins / antagonists & inhibitors
Repressor Proteins / metabolism
THP-1 Cells
Tumor Cells, Cultured
U937 Cells
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Enzyme Inhibitors
Ethylenediamines
MS023 compound
Pyrroles
RNA, Neoplasm
Repressor Proteins
PRMT1 protein, human
PRMT5 protein, human
Protein-Arginine N-Methyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding