Targeting mitochondrial vulnerabilities could help treat triple-negative breast cancer

A deeper understanding of mitochondrial function could create new opportunities for treating triple-negative breast cancer (TNBC), one of the most aggressive and difficult-to-treat forms of breast cancer. The complex relationship between mitochondrial dynamics, energy metabolism and cancer-cell survival is revealing potential targets that could support more personalized treatment strategies.

TNBC lacks several of the molecular targets used to treat other breast cancer subtypes, leaving chemotherapy as a central treatment option. However, the development of chemoresistance can significantly limit treatment effectiveness. Mitochondrial dysfunction may contribute to this resistance by helping cancer cells adapt their metabolism, manage cellular stress and avoid programmed cell death.

The balance between mitochondrial fission and fusion appears particularly important. Disruption of these processes can alter mitochondrial structure and function, interfere with oxidative phosphorylation, increase the production of reactive oxygen species and promote resistance to apoptosis. TNBC cells can also reprogram their energy metabolism, including through increased glycolysis and glutamine dependence, giving tumors metabolic advantages that support growth and survival.

These mitochondrial vulnerabilities present several potential therapeutic opportunities. Compounds including Mdivi-1, dynasore and cepharanthine have been explored for their ability to interfere with abnormal mitochondrial dynamics, including excessive fission, and encourage cancer-cell death. Other approaches focus on altered energy metabolism. Agents such as 2-deoxy-D-glucose (2DG), 3-bromopyruvate (3BP), clotrimazole and etomoxir can disrupt metabolic processes on which TNBC cells may depend.

Targeting mitochondria could also complement established treatments. Combining mitochondrial-directed agents with conventional chemotherapy may help increase anticancer activity and potentially address treatment resistance. Mitochondrial metabolism also interacts with the tumor microenvironment, suggesting that combining mitochondrial inhibitors with immunotherapies such as immune checkpoint inhibitors could provide another avenue for treatment.

Significant challenges remain. TNBC is highly heterogeneous, and its different subtypes have distinct metabolic and apoptotic characteristics. Treatments targeting mitochondrial function could also affect healthy tissues with substantial energy requirements, particularly the heart, brain and skeletal muscle. Technologies including nanoparticle-based drug delivery systems and antibody-drug conjugates could eventually help improve tumor-specific delivery and limit unwanted effects.