Modulation of oxidative phosphorylation augments antineoplastic activity of mitotic aurora kinase inhibition

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Uncontrolled mitosis is a hallmark of cancer, making mitotic kinases attractive therapeutic targets.
• Clinical trials of mitotic kinase inhibitors, including alisertib (MLN8237), have faced challenges due to limited efficacy.
• Alisertib, an aurora kinase A (AURKA) inhibitor, has shown potential but failed a Phase III trial.

Purpose of the Study:

• To identify biological processes that sensitize breast cancer cells to alisertib using genome-wide CRISPR/Cas9 screening.
• To investigate the mechanisms underlying alisertib's effects and explore combination therapies.
• To evaluate the efficacy of combining alisertib with metformin in preclinical models.

Main Methods:

• Genome-wide CRISPR/Cas9 screening in MDA-MB-231 breast cancer cells treated with alisertib.
• Mechanistic studies to assess intracellular ATP levels and cellular energy metabolism.
• In vitro and in vivo experiments combining alisertib with metformin.

Main Results:

• Alisertib treatment sensitized cancer cells to perturbations in oxidative phosphorylation (OXPHOS).
• Alisertib rapidly decreased intracellular ATP levels, increasing reliance on OXPHOS.
• Combination therapy with alisertib and metformin induced severe energy depletion and cell death, significantly enhancing tumor regression in vivo.

Conclusions:

• Targeting OXPHOS with metformin represents a potential strategy to enhance the therapeutic efficacy of mitotic kinase inhibitors like alisertib.
• Combined targeting of mitosis and cellular energy homeostasis offers a promising approach for breast cancer treatment.
• This combination therapy addresses the energy addiction induced by mitotic kinase inhibition, leading to improved anti-cancer effects.