Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer

SIMPLE SUMMARY: Mitochondria, often called “the powerhouse of the cell”, generate most of the energy required for all cellular processes. Mitochondria also provide a platform for multiple functions, including building essential macromolecules (nucleotides, proteins, and lipids), cell signaling, detoxification, and cell fate control. Studies have demonstrated that mitochondrial function is widely reprogrammed in breast cancers to promote tumor progression. Therefore, targeting mitochondria is currently one of the focal points in breast cancer research. Over 1000 proteins are involved with mitochondrial functions. The mitochondrial protease called ClpP plays a central role in mitochondrial protein quality control. Recently, ClpP agonists have emerged as a novel class of mitochondria-targeting drugs. Hyperactivating ClpP induces uncontrolled, but selective, degradation of ClpP substrates and disrupts mitochondrial functions, leading to growth inhibition of breast cancer cells, without adverse effect in non-malignant cells. The unique characteristics and mechanism of action of ClpP agonists provide new opportunities in breast cancer treatment. ABSTRACT: Breast cancer is the most frequently diagnosed malignancy worldwide and the leading cause of cancer mortality in women. Despite the recent development of new therapeutics including targeted therapies and immunotherapy, triple-negative breast cancer remains an aggressive form of breast cancer, and thus improved treatments are needed. In recent decades, it has become increasingly clear that breast cancers harbor metabolic plasticity that is controlled by mitochondria. A myriad of studies provide evidence that mitochondria are essential to breast cancer progression. Mitochondria in breast cancers are widely reprogrammed to enhance energy production and biosynthesis of macromolecules required for tumor growth. In this review, we will discuss the current understanding of mitochondrial roles in breast cancers and elucidate why mitochondria are a rational therapeutic target. We will then outline the status of the use of mitochondria-targeting drugs in breast cancers, and highlight ClpP agonists as emerging mitochondria-targeting drugs with a unique mechanism of action. We also illustrate possible drug combination strategies and challenges in the future breast cancer clinic.