PRMT1 inhibitor MS023 suppresses RNA splicing to sensitize small cell lung cancer to DNA damaging agents

Mansi K Aparnathi; Sami Ul Haq; Jonathan St-Germain; Kevin C J Nixon; Joseph Walton; Lifang Song; Safa Majeed; Parasvi S Patel; Ratheesh Subramaniam; Vivek Philip; Richard Marcellus; Dalia Barsyte-Lovejoy; Rima Al-Awar; Razqallah Hakem; Cheryl H Arrowsmith; Laurie Ailles; Brian Raught; Benjamin H Lok

doi:10.1016/j.neo.2025.101176

PRMT1 inhibitor MS023 suppresses RNA splicing to sensitize small cell lung cancer to DNA damaging agents

Neoplasia. 2025 Aug:66:101176. doi: 10.1016/j.neo.2025.101176. Epub 2025 May 23.

Authors

Mansi K Aparnathi¹, Sami Ul Haq², Jonathan St-Germain³, Kevin C J Nixon⁴, Joseph Walton⁵, Lifang Song¹, Safa Majeed⁶, Parasvi S Patel⁵, Ratheesh Subramaniam⁷, Vivek Philip¹, Richard Marcellus⁷, Dalia Barsyte-Lovejoy⁸, Rima Al-Awar⁹, Razqallah Hakem⁵, Cheryl H Arrowsmith¹⁰, Laurie Ailles⁵, Brian Raught³, Benjamin H Lok¹¹

Affiliations

¹ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Cancer Biology and Imaging, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
² Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Schulich School of Medicine & Dentistry, London, Ontario, Canada.
³ Protein Structure and Function, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁴ Cancer Biology and Imaging, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁵ Cancer Biology and Imaging, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Princess Margaret Cancer Research Tower, 101 College Street, Room 9-309, Toronto, ON, M5G 1L7, Canada.
⁶ Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Princess Margaret Cancer Research Tower, 101 College Street, Room 9-309, Toronto, ON, M5G 1L7, Canada.
⁷ Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, ON, M5G 0A3, Canada.
⁸ Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
⁹ Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, ON, M5G 0A3, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Chemistry, University of Toronto, Toronto, ON, M5S 3H6, Canada.
¹⁰ Protein Structure and Function, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Princess Margaret Cancer Research Tower, 101 College Street, Room 9-309, Toronto, ON, M5G 1L7, Canada; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
¹¹ Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Cancer Biology and Imaging, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 2374, Toronto, ON, M5S 1A8, Canada; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Princess Margaret Cancer Research Tower, 101 College Street, Room 9-309, Toronto, ON, M5G 1L7, Canada; Department of Radiation Oncology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address: benjamin.lok@uhn.ca.

Abstract

Small cell lung cancer (SCLC) is a highly aggressive form of cancer, commonly treated with DNA-damaging therapies such as chemotherapy and radiotherapy. Unfortunately, relapse occurs early and frequently, suggesting that epigenetic mechanisms may play a role in this aggressive behavior. Targeting these mechanisms during initial treatment could potentially enhance anti-cancer effects. This study investigated the combination of DNA-damaging treatments with a panel of Epigenetic Chemical Probes (EpiProbes). Among these, MS023, a PRMT inhibitor, showed the greatest synergy with cisplatin and etoposide across various SCLC cell lines. The cytotoxicity of MS023 was correlated with PRMT1 gene expression and protein levels. BioID analysis revealed that many PRMT1 interactors are involved in mRNA splicing. Mechanistic validation demonstrated that MS023 impaired RNA splicing, increased DNA:RNA hybrids, and caused DNA double-strand breaks (DSBs). When combined with ionizing radiation (IR), MS023 significantly increased DSBs, as indicated by γH2AX foci. Additionally, MS023 enhanced the effects of IR and the PARP inhibitor talazoparib, both in vitro and in vivo. Therefore, targeting PRMT1 in combination with DNA-damaging therapies presents a promising strategy to improve treatment outcomes for SCLC.

Keywords: Chemotherapy; Drug synergy; Epigenetics; PARP inhibitor; Radiation therapy; Small cell lung cancer, Poly(ADP-Ribose) polymerase.

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Cell Line, Tumor
DNA Damage* / drug effects
Drug Synergism
Etoposide / pharmacology
Gene Expression Regulation, Neoplastic / drug effects
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Mice
Protein-Arginine N-Methyltransferases* / antagonists & inhibitors
Protein-Arginine N-Methyltransferases* / genetics
Protein-Arginine N-Methyltransferases* / metabolism
RNA Splicing* / drug effects
Repressor Proteins* / antagonists & inhibitors
Small Cell Lung Carcinoma* / drug therapy
Small Cell Lung Carcinoma* / genetics
Small Cell Lung Carcinoma* / metabolism
Small Cell Lung Carcinoma* / pathology
Xenograft Model Antitumor Assays

Substances

Protein-Arginine N-Methyltransferases
PRMT1 protein, human
Repressor Proteins
Etoposide
Antineoplastic Agents