Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.08.11.552992

Synergistic effects of inhibitors targeting PI3K and Aurora Kinase A in preclinical inflammatory breast cancer models

Al-Ali, N.·Kment, J.·Young, S.·Craig, A.
View original source ↗Export metadata ↓

Abstract

BackgroundInflammatory 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. MethodsSUM149 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 ResultsThe 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. ConclusionsAlthough 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.

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Al-Ali, N., Kment, J., Young, S., Craig, A.. 2023-08-13. Synergistic effects of inhibitors targeting PI3K and Aurora Kinase A in preclinical inflammatory breast cancer models. https://doi.org/10.1101/2023.08.11.552992

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

EWSR1::ATF1 hyperactivation via TRIM11 depletion triggers lethal metabolic rewiring in clear cell sarcoma

Clear cell sarcoma (CCS) is an ultra-rare and aggressive soft tissue sarcoma driven by the EWSR1::ATF1 fusion oncoprotein. Currently, no effective and well-tolerated treatment options are available to CCS patients. Direct inhibition of fusion transcription factors is precluded by the absence of defined ligand-binding pockets, whereas their abundance is under the control of the ubiquitin-proteasome system (UPS), offering an alternative avenue for biology-guided treatment. Here we show the abundance of EWSR1::ATF1 is tightly regulated by the UPS, and that release of this constraint is lethal to CCS cells. A reporter-based CRISPR/Cas9 knockout screen of UPS components identified TRIM11 as an E3 ligase that regulates turnover of EWSR1::ATF1, which it recognises as a neosubstrate without altering wild-type EWSR1 or ATF1. Depletion of TRIM11 increased nuclear fusion protein abundance, amplified the fusion-driven transcriptional programs and reduced viability. Proteomic analysis identified the cataplerotic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1), a direct EWSR1::ATF1 target, as the key mediator of lethal effects of fusion hyperactivation. Extracellular flux analysis, isotope tracing and quantitative metabolomics revealed excessive cataplerotic carbon withdrawal and impaired oxidative phosphorylation as the underlying mechanism. In patient tumors, high PCK1 expression associated with metastatic transcriptome programs and disease presentation, as well as shorter survival. Taken together, we report that hyperactivation of EWSR1::ATF1 opens a metabolic vulnerability, establishing TRIM11 as an actionable dependency and PCK1 as a candidate prognostic biomarker in CCS.

cancer biology↗
bioRxiv2026

Glycolysis and interferon transcription in melanoma immunotherapy

Glycolysis and interferon signalling have both been associated with responses to PD-1 blockade, but their joint transcriptional relationship with treatment outcome remains uncertain. We examined whether a state with high glycolysis and low interferon- response was associated with reduced disease control in melanoma. Fixed Hallmark gene sets were scored by single-sample gene set enrichment analysis in GSE91061, GSE78220 and an additional Liu cohort. Disease control analyses included 47, 26 and 100 patients. Conditional odds ratios for the joint state were 6.06 (exact 95% confidence interval, 1.04 to 65.61), 0.35 (0.026 to 3.11) and 1.03 (0.39 to 2.73), respectively. Holm-adjusted P values for the two initial comparisons were 0.073 and 0.365. The additional exploratory P value was 1.000. Continuous models and analyses that omitted each patient in turn did not provide consistent evidence of an adverse association. IFN scores were negatively correlated with DNA-derived tumour purity in 102 patients (Spearman {rho} = -0.671). Among 40 patients with paired biopsies, disease control was associated with higher on-treatment IFN scores after baseline adjustment, although the paired subset had lower baseline glycolysis than patients without paired profiles. In patient-level single-cell analyses, the baseline CD8 T cell correlation weakened when an alternative rank score used a common gene background. The defined joint state was not consistently associated with poorer disease control across cohorts. Bulk IFN scores were related to tumour purity, and cellular correlations were sensitive to scoring choices. These transcriptomic results do not measure pyruvate concentration, glycolytic flux or STAT1 pyruvylation.

cancer biology↗
bioRxiv2026

Psychoneuroimmunology of Viral Hepatitis and Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Hepatocellular carcinoma (HCC) and viral hepatitis (VH) are recognized primarily as hepatic diseases, yet they impose a substantial neuropsychiatric disorders (NPDs) encompassing depression, anxiety, cognitive impairment, and fatigue. Whether these manifestations reflect psychological reactions or biologically grounded psychoneuroimmune dysfunction remains poorly understood. Here, we present a pre-registered systematic review and meta-analysis (PROSPERO 2026 CRD420251081757) synthesizing evidence from 24 studies combining psychosocial outcomes with immune dysregulation markers across HCC and VH populations. Bibliometric and network analyses identified a growing psychoneuroimmunology research hub linking cytokine signaling, microglial activation, blood-brain barrier (BBB) disruption, and gut-liver-brain axis dysregulation to the neuropsychiatric phenotype of these diseases. Meta-analysis revealed a pooled hazard ratio (HR) of 1.92 (95% CI: 1.09-3.39) for adverse outcomes in HCC and a pooled HR of 2.28 (95% CI: 1.48-3.52) for depression associated to genetic variants in VH. TNF-a, but not IL-6, showed a tendency toward lower levels in VH patients with versus without NPDs, suggesting differential inflammatory roles. The literature, however, remains fragmented by heterogeneous designs and a paucity of longitudinal data. A psychoneuroimmunological approach, integrating immune, endocrine, neural, and psychosocial dimensions, is essential for capturing the full systemic impact of HCC and VH and should inform future mechanistic research and multidisciplinary clinical strategies.

cancer biology↗