Abstract 365: A dual mechanism of sensitivity to PLK4 inhibition by RP-1664 in neuroblastoma
Bibliographic record
Abstract
Abstract Introduction: High-risk neuroblastoma (HRNB) is a pediatric tumor with poor prognosis and limited treatment options. Recently, a novel therapeutic hypothesis for HRNB was proposed based on synthetic lethality between inhibition of polo-like kinase 4 (PLK4) and high expression of TRIM37 - a gene encoded on chromosome 17q, whose gain is among the most frequent genomic alterations in HRNB1, 2. This synthetic lethality depends on PLK4 inhibition-driven loss of centrioles, which in TRIM37-overexpressing tumor cells disrupts mitotic spindle assembly, and causes cell death through mitotic delay and p53 activation. Interestingly, partial PLK4 inactivation by low doses of pharmacological inhibitors is known to have an opposite effect on centrioles - increasing their number3. Here we report that both centriole amplification and centriole loss contribute to an exquisite sensitivity of HRNB models to RP-1664, a first-in-class selective and orally available inhibitor of PLK4. Methods: RP-1664 sensitivity and cellular consequences of PLK4 inhibition were evaluated in a panel of HRNB cell lines and normal immortalized cells with or without TRIM37 overexpression and functional TP53. To that end, cell growth assays, immunofluorescence, immunoblotting and live cell imaging were used. CRISPR/Cas9 genomic screening was employed to map genes modulating RP-1664 sensitivity. RP-1664 in vivo efficacy was assessed in HRNB mouse xenograft models. Results: RP-1664 induced expected phenotypes of PLK4 inhibition in human cells, including an increase in PLK4 protein level, p53/p21 activation, centriole amplification at lower concentrations, and centriole loss at higher concentrations. HRNB cell lines showed general hypersensitivity to RP-1664, including at concentrations leading to centriole amplification. While sensitivity at higher RP-1664 concentrations depended on TRIM37 and TP53, and was associated with a delay in mitosis, sensitivity at lower concentrations was TRIM37- and TP53-independent. CRISPR screens and live cell imaging after low-dose RP-1664 treatment revealed that HRNB cells, unlike normal immortalized cells, were unable to compensate for excess centrioles by their inactivation or clustering, and succumbed to multipolar mitoses. In vivo, RP-1664 showed robust efficacy at well tolerated doses in HRNB models and at plasma exposures consistent with centriole amplification. Conclusion: HRNB cell models are hypersensitive to centriole amplification induced by low levels of PLK4 inhibition as well as to centriole loss at higher PLK4 inhibitor levels, warranting the investigation of RP-1664 in clinical trials with neuroblastoma patients. 1. Yeow, Z. Y. et al., Nature 585, 447-452 (2020). 2. Meitinger, F. et al., Nature 585, 440-446 (2020). 3. Tkach, J. M. et al., Elife 11, e73944 (2022). Citation Format: Isabel Soria-Bretones, Matias Casás-Selves, Elliot Goodfellow, Ariya Shiwram, Nancy Laterreur, Li Li, Cathy Carron, Julian Bowlan, Hyeyeon Kim, Danielle Henry, Alejandro Álvarez-Quilon, Frédéric Vallée, Artur Veloso, Jordan T. Young, Stephen J. Morris, C. Gary Marshall, Michal Zimmermann. A dual mechanism of sensitivity to PLK4 inhibition by RP-1664 in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 365.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".