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

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

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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