Abstract A32: Selective inhibition of AuroraA by LY3295668 erbumine in neuroblastoma models induces apoptosis through a combination of S-phase DNA damage and mitotic arrest
Bibliographic record
Abstract
Abstract Aurora kinase A (AuroraA) is a serine/threonine protein kinase critical for centrosome maturation, mitotic spindle formation, and spindle checkpoint activation. Aberrant expression of AuroraA promotes tumor initiation and disease progression, making it a promising therapeutic target in several cancer types. However, recent clinical trials of purported selective AuroraA inhibitors failed due to lack of efficacy and/or hematologic toxicity, likely due to concurrent inhibition of Aurora kinase B (AuroraB). Selective AuroraA inhibition leads to mitotic arrest and apoptosis, while AuroraB inhibition causes persistent DNA endoreduplication and polyploidy leading to genomic instability. LY3295668 erbumine (LY3295668) is a selective AuroraA inhibitor with preclinical activity in multiple models of cancer including neuroblastoma (NBL). High-risk NBL, a devastating pediatric cancer with few effective treatment options, is mainly stratified by MYCN amplification status. In NBL, AuroraA stabilizes N-MYC post-transcriptionally; moreover, AuroraA also controls N-MYC-dependent transcription during S-phase. Here, we evaluated LY3295668 in multiple NBL cell lines and in vivo mouse models where treatment resulted in apoptosis and tumor regressions, respectively. We compared LY3295668 to alisertib (a dual AuroraA/B inhibitor) in multiple cell-based assays that differentiate AuroraA activity from that of AuroraB and showed that LY3295668 has a distinct pharmacologic profile from alisertib. In addition, we determined the mechanism of action for LY3295668 includes DNA damage prior to mitotic block. Our results further support that AuroraA controls MYC-dependent transcription in S-phase and selective inhibition of AuroraA with LY3295668 promotes transcription-replication conflicts leading to DNA damage. In addition to AuroraA-mediated mitotic arrest, this DNA damage may contribute to the hypersensitivity of MYC-driven tumors such as NBL. In summary, LY3295668 is a selective AuroraA inhibitor with a dual mechanism of action in NBL involving DNA damage in S-phase and a cell cycle block in mitosis. These combined activities contribute to sensitivity of preclinical NBL models. Citation Format: Michele Dowless, Jill Kremer, Caitlin Lowery, Xueqian Gong, Joseph Klahn, Jennifer Stephens, Yu-Hua Hui, Wayne Blosser, Ricardo Martinez, Jian Du, Louis Stancato. Selective inhibition of AuroraA by LY3295668 erbumine in neuroblastoma models induces apoptosis through a combination of S-phase DNA damage and mitotic arrest [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A32.
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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) | 0.001 | 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 | 0.000 |
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".