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

  • Nat Commun. 2026 Jun 13. doi: 10.1038/s41467-026-74061-5.
Isabel Soria-Bretones  #  1 ,  Matias Casás-Selves  #  1 ,  Minu Samanta  #  2 ,  David Groff  #  2 ,  Jayne Murray  3  4 ,  Jamie I Fletcher  3  4 ,  Alvin Farrel  2 ,  Steven Pastor  2 ,  Khushbu Patel  2 ,  Elliot Goodfellow  1 ,  Li Li  1 ,  Cathy Caron  1 ,  Ariya Shiwram  1 ,  Hyeyeon Kim  1 ,  Danielle Henry  1 ,  Nancy Laterreur  1 ,  Julian Bowlan  5 ,  Kateryna Krytska  2 ,  Steven B Neuhauser  6 ,  Timothy M Stearns  6 ,  Jeffrey A Schubert  7 ,  Jinhua Wu  7 ,  Lea F Surrey  7 ,  Daniel Martinez  7 ,  Crystal Mak  3 ,  Jennifer Brand  3 ,  Caitlin Wesley  3 ,  Klaartje Somers  3  4 ,  Alejandro Álvarez-Quilón  1 ,  Frédéric Vallée  1 ,  Parham Nejad  5 ,  Joseph D Schonhoft  5 ,  Joanna Li  1 ,  Artur Veloso  5 ,  Jordan T F Young  1 ,  Marc L Hyer  5 ,  Stephen J Morris  1 ,  Yael P Mossé  2  8 ,  C Gary Marshall  2 ,  Michelle Haber  3  4 ,  Michal Zimmermann  9 ,  John M Maris  10  11
Affiliations
  • 1. Repare Therapeutics, St. Laurent, QC, Canada.
  • 2. Divison of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 3. Children's Cancer Institute at Minderoo Children's Comprehensive Cancer Centre, Sydney, NSW, Australia.
  • 4. School of Clinical Medicine, UNSW Sydney, Kensington, NSW, Australia.
  • 5. Repare Therapeutics, Cambridge, MA, USA.
  • 6. The Jackson Laboratory, Bar Harbor, ME, USA.
  • 7. Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 8. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • 9. Repare Therapeutics, St. Laurent, QC, Canada. [email protected].
  • 10. Divison of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA. [email protected].
  • 11. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • # Contributed equally.
PMID: 42288516 DOI: 10.1038/s41467-026-74061-5
Abstract

It was recently shown that inhibition of polo-like kinase 4 (PLK4) induces 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 defining 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-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 monotherapy showed robust anti-tumor activity in 14/15 human neuroblastoma-derived xenograft models, and significantly extended survival in a transgenic MYCN-driven murine model of neuroblastoma. RP-1664 combined with GD2-directed chemoimmunotherapy resulted in maintained complete responses in 6/9 mice with established MYCN-driven murine neuroblastomas. These data support clinical development of PLK4 inhibitors for high-risk neuroblastoma and Other cancers with somatically acquired TRIM37 overexpression.

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