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PRMT5 inhibition disrupts splicing and stemness in glioblastoma

Patty Sachamitr1,2, Jolene C Ho2, Felipe E Ciamponi3,4

  • 1Developmental and Stem Cell Biology Program and Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.

Nature Communications
|February 13, 2021
PubMed

Insights

Targeting Protein arginine methyltransferase 5 (PRMT5) with inhibitors like LLY-283 suppressed glioblastoma stem cell growth. This approach shows promise for treating this deadly brain cancer by disrupting splicing and improving survival in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Stem Cell Research

Background:

  • Glioblastoma (GBM) is an aggressive brain tumor characterized by cancer stem cells (CSCs) that drive tumor growth and treatment resistance.
  • Protein arginine methyltransferase 5 (PRMT5) is implicated in GBM pathogenesis and represents a potential therapeutic target.

Purpose of the Study:

  • To investigate the efficacy of pharmacological PRMT5 inhibition in patient-derived GBM stem cell cultures.
  • To elucidate the molecular mechanisms underlying PRMT5 inhibition in GBM.
  • To evaluate the therapeutic potential of brain-penetrant PRMT5 inhibitors in preclinical GBM models.

Main Methods:

  • Utilized two PRMT5 inhibitors (GSK591, LLY-283) against 46 patient-derived GBM stem cell cultures.
  • Performed transcriptome-wide splicing analysis to assess the impact of PRMT5 inhibition.
  • Developed and validated a GBM splicing signature.
  • Assessed the brain penetrance and therapeutic efficacy of LLY-283 in orthotopic patient-derived xenograft mouse models.

Main Results:

  • PRMT5 inhibition significantly suppressed GBM stem cell growth, with higher sensitivity observed in the proneural subtype.
  • PRMT5 inhibition led to widespread splicing disruptions, notably affecting cell cycle-related genes.
  • A specific GBM splicing signature correlated with response to PRMT5 inhibition.
  • The PRMT5 inhibitor LLY-283 demonstrated brain penetrance and significantly extended survival in preclinical GBM xenograft models.

Conclusions:

  • Pharmacological inhibition of PRMT5 is a viable strategy for suppressing GBM stem cell growth.
  • PRMT5 inhibition exerts its effects through widespread disruption of RNA splicing.
  • Brain-penetrant PRMT5 inhibitors, such as LLY-283, hold significant potential for clinical development in GBM treatment.

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