Targeting cancer cell mitochondrial redox metabolism to improve radiation and chemotherapy responses

We are seeking to enhance efficacy of radiation and chemotherapies that are currently being used to treat lung and breast cancers to improve survival. Finding a universal vulnerability of cancer cells has been a goal in cancer therapy. Cancer cells have been found to reprogram their metabolism to provide them with an advantage in survival. However, cancer cells may become overly reliant on this altered metabolism such that targeting a key component, like pyruvate import into the mitochondria, results in greater killing of cancer cells. Previous work showed that disrupting mitochondrial function by reducing mitochondrial membrane potential with a small, charged molecule increased oxidation and selectively killed breast cancer cells. Current work shows that blocking mitochondrial pyruvate import through the inhibition of the mitochondrial pyruvate carrier shows selective killing and radiation sensitization in breast and lung cancer cells.

Blocking pyruvate import into mitochondria shows an increase in oxidation sensitive probes, an increase in cell death that is specific for cancer cells of multiple tissue origins, over normal epithelial cells from those tissues, and enhances both radiation and current standard of care chemotherapies for cancer cell killing. This has been shown through both chemical inhibition with drug and genetic knockout by CRISPR. These findings provide a biochemical rationale for using mitochondrial disruptions to selectively sensitize breast and lung cancers to chemotherapy and radiation induced oxidative stress.