Synergistic effects of inhibitors targeting PI3K and Aurora Kinase A in preclinical inflammatory breast cancer models
Bibliographic record
Abstract
Abstract Background Inflammatory breast cancer (IBC) is an aggressive clinical subtype of breast cancer often diagnosed in young women. Lymph node and distant metastases are frequently detected at diagnosis of IBC, and improvements in systemic therapies are needed. For IBC that lack hormone or HER2 expression, no targeted therapies are available. Since the phosphatidyl inositol 3’ kinase (PI3K) pathway is frequently deregulated in IBC, some studies have tested the pan PI3K inhibitor Buparlisib (BKM120). Although the SUM149 IBC cell line was resistant to Buparlisib, a functional genomic screen showed that silencing of Aurora kinase A (AURKA) sensitized cells to killing by Buparlisib. In this study, we tested whether combination treatments of PI3K and AURKA inhibitors act synergistically to kill IBC cells and tumors. Methods SUM149 cells were treated with increasing doses of PI3K inhibitor Buparlisib (BKM120) and AURKA inhibitor Alisertib as monotherapies or combination therapies. Effects on target pathways, cytotoxicity, cell cycle, soft agar colony growth and cell migration were analyzed. The individual and combined treatments were also tested in a mammary orthotopic SUM149 tumor xenograft model to measure effects on tumor growth and metastasis Results The SUM149 IBC cell line treated with Buparlisib showed reduced PI3K/AKT activation but no significant skewing of cell cycle progression. Parallel studies of Alisertib treatment showed that AURKA inhibition led to a significant block in G2/M transition in SUM149 cells. In cytotoxicity assays, Buparlisib and Alisertib combination treatments were highly synergistic compared to monotherapy controls. Evidence of synergy between Buparlisib and Alisertib also extended to soft agar colony growth and wound healing motility in SUM149 cells. The combination of Buparlisib and Alisertib also reduced IBC tumor growth in mammary orthotopic xenograft assays and reduced spontaneous metastases development in lung tissue. Conclusions Although SUM149 IBC cells were relatively resistant to killing by the PI3K inhibitor Buparlisib, our study showed that co-targeting the mitotic kinase AURKA with Alisertib synergized to limit IBC cell growth and motility, as well as IBC tumor growth and metastasis.
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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 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 | 0.002 |
| 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".