The PLK4 inhibitor RP-1664 demonstrates potent single-agent efficacy in neuroblastoma models through a dual mechanism of sensitivity

  • Res Sq. 2025 Jul 29:rs.3.rs-7014295. doi: 10.21203/rs.3.rs-7014295/v1.
John Maris  1 ,  Isabel Soria-Bretones  2 ,  Matias Casás-Selves  2 ,  Minu Samanta  3 ,  David Groff  3 ,  Jayne Murray  4 ,  Jamie Fletcher  5 ,  Alvin Farrel  6 ,  Steven Pastor  6 ,  Khushbu Patel  7 ,  Elliot Goodfellow Goodfellow  2 ,  Li Li  2 ,  Cathy Caron  2 ,  Ariya Shiwram  2 ,  Hyeyeon Kim  2 ,  Danielle Henry  2 ,  Nancy Laterreur  2 ,  Julian Bowlan  8 ,  Kateryna Krytska  7 ,  Steven Neuhauser  9 ,  Timothy Stearns  10 ,  Jeffrey Schubert  6 ,  Jinhua Wu  6 ,  Lea Surrey  6 ,  Alejandro Álvarez-Quilón  2 ,  Frédéric Vallée  2 ,  Parham Nejad  8 ,  Joseph Schonhoft  8 ,  Joanna Li  2 ,  Artur Veloso  11 ,  Jordan Young  2 ,  Marc Hyer  8 ,  Stephen Morris  2 ,  Yael P Mossé  6 ,  Gary Marshall  11 ,  Michelle Haber  12 ,  Michal Zimmermann  11
Affiliations
  • 1. University of Pennsylvania and Children's Hospital of Philadelphia.
  • 2. Repare Therapeutics, Inc., St. Laurent, QC, Canada.
  • 3. Children's Hosp of Philadelphia.
  • 4. Children's Cancer Institute.
  • 5. Children's Cancer Institute Australia.
  • 6. Children's Hospital of Philadelphia.
  • 7. Children's Hosptial of Philadelphia.
  • 8. Repare Therapeutics, Inc., Cambridge, MA, USA.
  • 9. The Jackson Laboratory.
  • 10. The Jackson Laboratory, Bar Harbor, ME, USA.
  • 11. Repare Therapeutics.
  • 12. Experimental Therapeutics Program.
PMID: 40766251 DOI: 10.21203/rs.3.rs-7014295/v1
Abstract

It was recently shown that inhibition of polo-like kinase 4 (PLK4) induces TP53-dependent synthetic lethality in cancers with chromosome 17q-encoded TRIM37 copy number gain due to cooperative regulation of centriole duplication and mitotic spindle nucleation. We show here that chromosome 17q/TRIM37 gain is a pathognomonic feature of high-risk neuroblastoma and renders patient-derived cell lines hypersensitive to the novel PLK4 Inhibitor RP-1664. We demonstrate that centriole amplification at low doses of RP-1664 contributes to this sensitivity in a TRIM37- and TP53-independent fashion. CRISPR screens and live cell imaging reveal that upon centriole amplification, neuroblastoma cells succumb to multipolar mitoses due to an inability to cluster or inactivate supernumerary centrosomes. RP-1664 showed robust anti-tumor activity in 14/15 neuroblastoma xenograft models and significantly extended survival in a transgenic murine neuroblastoma model. These data support biomarker-directed clinical development of PLK4 inhibitors for high-risk neuroblastoma and Other cancers with somatically acquired TRIM37 overexpression.

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