Abstract 161: Regulation of Abl at mitotic centrosomes and survival by ILK in glioblastoma cells
Bibliographic record
Abstract
Abstract Many cancer cells possess supernumerary centrosomes, having more than one centrosome at each pole during mitosis which can lead to aberrant mitotic division and cell death. To prevent this fate, cancer cells cluster their centrosomes at two poles during division to divide in a pseudobipolar manner. As the presence of supernumerary centrosomes is rare in normal cells, targeting the declustering of supernumerary centrosomes in cancer cells is a promising strategy for cancer treatment. Integrin-linked kinase (ILK) is an oncogenic protein and chemotherapeutic target shown to be found at the centrosome where it has a role in facilitating centrosome clustering. Inhibition of ILK, via an anti-ILK chemotherapeutic drug QLT-0267, has been shown to increase centrosome declustering causing mitotic arrest and cell death. However, not all cancers cells are susceptible to anti-ILK treatment alone. Therefore, we investigate a combination treatment strategy targeting ILK and another oncogenic kinase, Abelson kinase (Abl). Both ILK and Abl are involved in cancer cell survival, regulated by the same signalling pathways and share common binding partners that occur at the centrosome and are critical for mitosis. The ILK inhibitor QLT-0267 induced a significant sub-G1 peak following propidium iodide FACS analysis and an increase in MTT labelling, indicating that QLT-0267 significantly decreased survival in glioblastoma cell lines. These effects were augmented in the presence of imatinib, an Abl inhibitor. Moreover, QLT-0267 and imatinib, in combination, significantly increased mitotically arrested cells over the ILK inhibitor alone. Increased levels of cytosolic Abl have been associated with its transformative abilities. The ILK inhibitor effects on survival correlated with its ability to decrease cytosolic Abl levels and inhibited Abl’s localization to mitotic centrosomes in dividing glioblastoma cells. These effects were reversed by the proteasomal inhibitor MG132 (a drug that inhibits the degradation of Abl). Together these results indicate that combination treatment with QLT-0267 and imatinib are more effective then QLT-0267 alone at decreasing successful mitoses and survival in glioblastoma cells. Future studies will unravel the relationship between these oncogenic kinases at centrosomes and its effect on cancer cell cycle progression and survival. Citation Format: Jonathan Dresselhuis, Maddisen Brown, Nicole Robinson, Jacqueline Tan, Michael E. Cox, Julia Mills. Regulation of Abl at mitotic centrosomes and survival by ILK in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 161.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 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 teacher head, 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".