Aurora Kinases as Therapeutic Targets in Multiple Myeloma.
Bibliographic record
Abstract
Abstract BACKGROUND: We have previously found that in multiple myeloma there is amplification of the centrosome, the organelle that nucleates the mitotic spindle. We have reported that RHAMM is a component of the centrosome which interacts with TPX2, the protein that targets Aurora A kinase to the mitotic spindle. We have also shown that RHAMM expression and alternative splicing in myeloma correlate with centrosome amplification, aggressive disease and poor survival. These findings led us to speculate that Aurora A and possibly other Aurora kinases are potential therapeutic targets in myeloma. METHODS: We examined the expression of Aurora A, B and C kinases in 5 myeloma cell lines and autoMACS-purified CD138+ myeloma bone marrow plasma cells from 20 patients. We assessed the anti-proliferative and pro-apoptotic effects of Aurora A knockdown in myeloma cell lines with RNA interference. We investigated the anti-myeloma activity of two potent, selective Aurora kinase inhibitors, VE-465 (Merck/Vertex) and AZD1152 (AstraZeneca), in 5 myeloma cell lines, in CD138+ bone marrow plasma cells from 2 myeloma patients, and in a NOD/SCID murine xenograft model. RESULTS: Aurora A, B and C kinases are ubiquitously expressed in both myeloma cell lines and myeloma bone marrow plasma cells. Expression levels vary among patients. Aurora A and B are expressed in myeloma plasma cells at levels comparable to that seen in the CD138- cells from the same marrow sample, and comparable to the levels seen in normal marrow from control individuals. Aurora C, while expressed at low levels, is consistently ectopically overexpressed in myeloma plasma cells relative to coexisting CD138- cells and normal marrow. In myeloma cell lines, Aurora A knockdown with RNA interference induces apoptosis and cell killing. In all five myeloma cell lines tested, and in myeloma bone marrow plasma cells from two patients, both VE-465 and AZD1152 induce apoptosis and myeloma cell killing at nanomolar concentrations, to varying degrees (20–80% reduction in cell viability). VE-465 is known to inhibit all three Aurora kinases with comparable specificity, while AZD1152 is known to inhibit Aurora B and C more selectively than Aurora A. Despite these differences in activity, both compounds have comparable pre-clinical efficacy against myeloma. Myeloma cell lines treated with either agent demonstrate a phenotype consistent with target inhibition. Both drugs show additive effects on killing of cell lines and primary myeloma cells when combined with dexamethasone, even in dexamethasone-resistant cells. Anti-myeloma activity was seen with single agent Aurora kinase inhibition in the murine model, at well tolerated doses. CONCLUSIONS: Aurora kinases are potential therapeutic targets in myeloma. Aurora kinase inhibitors comprise an emerging class of anti-cancer drug therapy that deserves further evaluation for myeloma patients.
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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) | 0.000 | 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".