The PLK4 inhibitor RP-1664 demonstrates potent efficacy in neuroblastoma preclinical models through a dual mechanism of sensitivity
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.
Article Details
Authors (42)
Isabel Soria-Bretones
Matias Casás-Selves
Minu Samanta
David Groff
Jayne Murray
Children’s Cancer Institute
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
Children’s Cancer Institute
Michal Zimmermann
John M. Maris