Alisertib and Barasertib Induce Cell Cycle Arrest and Mitochondria-Related Cell Death in Multiple Myeloma with Enhanced Efficacy Through Sequential Combination with BH3-Mimetics and Panobinostat

TL;DR

Alisertib and barasertib, which target Aurora kinases, show promise in killing multiple myeloma cells, especially when combined with other drugs in a specific sequence.

Contribution

The study reveals the mechanisms of Aurora kinase inhibitors in myeloma and identifies effective sequential drug combinations.

Findings

Alisertib and barasertib induce cell cycle arrest and mitochondrial cell death in multiple myeloma cells.

Sequential combinations with BH3-mimetics and panobinostat show synergistic effects, while simultaneous combinations are antagonistic.

Low-dose alisertib remains toxic to Bax/BakDKO cells, suggesting non-apoptotic cell death pathways.

Abstract

Multiple myeloma (MM) remains a challenging disease despite significant therapeutic advances achieved with the introduction of novel therapies, prompting the search for new agents with unique and targeted mechanisms of action. Here, we investigated the selective Aurora kinase inhibitors alisertib (Aurora A) and barasertib (Aurora B) as potential anti-myeloma candidates. Our results demonstrate that both drugs exhibit anti-myeloma activity in vitro, and their sequential combination with BH3-mimetics and panobinostat could be beneficial. Therefore, these findings open the door to further explore selective inhibition of Aurora proteins as a targeted therapy in MM.

Background: The treatment landscape for multiple myeloma (MM) has significantly evolved in recent decades with novel therapies like proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. However, MM remains incurable, necessitating new pharmacological strategies. Mitotic kinases, such as Aurora proteins, have emerged as potential targets. Selective inhibitors of Aurora A and B,- alisertib (MLN8237) and barasertib (AZD1152), respectively, have shown anti-myeloma activity in preclinical studies, with alisertib demonstrating modest efficacy in early clinical trials. Methods and Results: This study investigated the mechanisms of action of alisertib and barasertib and their combination with antitumor agents in a panel of five MM cells lines. Both drugs induced cell cycle arrest phase and abnormal nuclear morphologies. Alisertib caused prolonged mitotic arrest, whereas barasertib induced transient arrest, both resulting in the activation of mitotic catastrophe. These findings revealed three potential outcomes: cell death, senescence, or polyploidy. High mitochondrial reactive oxygen species (mROS) were identified as possible drivers of cell death. Caspase inhibition reduced caspase-3 activation but did not prevent cell death. Interestingly, alisertib at low doses remained toxic to Bax/BakDKO cells, although mitochondrial potential disruption and cytochrome c release were observed. Sequential combinations of high-dose Aurora kinase inhibitors with BH3-mimetics, and in specific cases with panobinostat, showed a synergistic effect. Conversely, the simultaneous combination of alisertib and barasertib showed mostly antagonistic effects. Conclusions: Alisertib and barasertib emerge as potential in vitro candidates against MM, although further studies are needed to validate their efficacy and to find the best combinations with other molecules.

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