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

Mansi K Aparnathi1, Sami Ul Haq2, Jonathan St-Germain3

  • 1Radiation 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.

Neoplasia (New York, N.Y.)
|May 25, 2025
PubMed

Insights

Targeting PRMT1 with MS023 enhances DNA-damaging therapies for small cell lung cancer (SCLC). This combination therapy shows promise in overcoming early relapse and improving treatment outcomes for SCLC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Small cell lung cancer (SCLC) is an aggressive malignancy with high relapse rates after standard DNA-damaging treatments.
  • Epigenetic mechanisms are implicated in SCLC's aggressive behavior and treatment resistance.
  • Targeting epigenetic pathways may enhance the efficacy of current SCLC therapies.

Purpose of the Study:

  • To investigate the synergistic potential of combining DNA-damaging agents with epigenetic chemical probes (EpiProbes) in SCLC.
  • To identify specific epigenetic targets and inhibitors that enhance chemotherapy and radiotherapy effects.
  • To elucidate the mechanisms by which epigenetic modulation impacts SCLC response to DNA damage.

Main Methods:

  • Screening of EpiProbes in combination with cisplatin and etoposide across diverse SCLC cell lines.
  • Assessment of cytotoxicity, PRMT1 expression, and protein levels.
  • BioID analysis to identify PRMT1 interactors.
  • Mechanistic studies involving RNA splicing, DNA:RNA hybrid formation, and DNA double-strand breaks (DSBs) assessment (γH2AX foci).
  • In vitro and in vivo evaluation of combination therapy with ionizing radiation (IR) and talazoparib.

Main Results:

  • The PRMT inhibitor MS023 demonstrated significant synergy with cisplatin and etoposide in SCLC cells.
  • MS023 cytotoxicity correlated with PRMT1 expression.
  • PRMT1 interactors are predominantly involved in mRNA splicing.
  • MS023 treatment led to impaired RNA splicing, increased DNA:RNA hybrids, and induced DSBs.
  • Combination of MS023 with IR or talazoparib enhanced anti-cancer effects both in vitro and in vivo.

Conclusions:

  • Targeting PRMT1 with MS023 represents a potent strategy to enhance DNA-damaging therapies for SCLC.
  • The combination therapy mechanism involves impaired RNA splicing and increased DNA damage.
  • This approach holds promise for improving treatment outcomes and overcoming relapse in SCLC.
Keywords:
ChemotherapyDrug synergyEpigeneticsPARP inhibitorRadiation therapySmall cell lung cancer, Poly(ADP-Ribose) polymerase

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