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

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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Publication Details

Journal
Nature Communications
Published
2026-06-13
DOI
https://doi.org/10.1038/s41467-026-74061-5
Primary Topic
Neuroblastoma Research and Treatments
Type
article
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article

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

Frédéric Vallée, David Groff, John M. Maris, Klaartje Somers et al.
Nature Communications
Neuroblastoma Research and Treatments
article

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

Frédéric Vallée, David Groff, John M. Maris, Klaartje Somers, Jeffrey Schubert, Alejandro Álvarez-Quilón, Elliot Goodfellow, Isabel Soria‐Bretones, Timothy M. Stearns, Parham Nejad, Yaël P. Mossé, Michal Zimmermann, Lea F. Surrey, Julian Bowlan, Alvin Farrel, H Kim, Michelle Haber, Jinhua Wu, Matias Casás‐Selves, Joanna Li, Minu Samanta, Marc L. Hyer, Steven Pastor, Jordan T.F. Young, Jamie I. Fletcher, Steven B. Neuhauser, Ariya Shiwram, Li Li, Danielle Henry, Khushbu Patel, Crystal Mak, Stephen J. Morris, Nancy Laterreur, Daniel Martinez, Jayne Murray, Artur Veloso, Kateryna Krytska, Cathy Caron, Jennifer Brand, C. Gary Marshall, Caitlin Wesley, Joseph D. Schonhoft
article en

Abstract

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.

Nature Communications
Good health and well-being
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Neuroblastoma Research and Treatments
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