The PLK4 inhibitor RP-1664 demonstrates potent efficacy in neuroblastoma preclinical models through a dual mechanism of sensitivity
- Isabel Soria-Bretones
- Matias Casás-Selves
- Minu Samanta
- David Groff
- Jayne Murray
- Jamie I. Fletcher
- Alvin Farrel
- Steven Pastor
- Khushbu Patel
- Elliot Goodfellow
- Li Li
- Cathy Caron
- Ariya Shiwram
- Hyeyeon Kim
- Danielle Henry
- Nancy Laterreur
- Julian Bowlan
- Kateryna Krytska
- Steven B. Neuhauser
- Timothy M. Stearns
- Jeffrey A. Schubert
- Jinhua Wu
- Lea F. Surrey
- Daniel Martinez
- Crystal Mak
- Jennifer Brand
- Caitlin Wesley
- Klaartje Somers
- Alejandro Álvarez-Quilón
- Frédéric Vallée
- Parham Nejad
- Joseph D. Schonhoft
- Joanna Li
- Artur Veloso
- Jordan T. F. Young
- Marc L. Hyer
- Stephen J. Morris
- Yael P. Mossé
- C. Gary Marshall
- Michelle Haber
- Michal Zimmermann
- John M. Maris
2026-06-13
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.