IDENTIFICATION OF MUTATED CANCER GENES THAT ARE SENSITIVE TO MITOCHONDRIAL DAMAGING DRUGS

Cancer cells exhibit an altered mitochondrial phenotype comprised of decreased oxidative phosphorylation and concomitant increases in glycolysis (Warburg metabolism). A wealth of molecular research in the last fifty years has demonstrated that mitochondria also function as gatekeepers for the activation of apoptosis, a non- inflammatory cell death pathway. The activation of apoptosis has long been considered a desirable method of limiting tumor progression and removing cancerous cells. Apoptosis can be activated in several different ways. Recently, it has been discovered that over-activating mitophagy (a normal cellular program used for maintaining mitochondrial health by removing organelles that are too damaged to function properly) can trigger apoptosis. It has been shown that acute iron chelation (removal) can hyper-activate mitophag y in C. elegans. Neoplastic cells, which are generally more sensitive to cellular stresses, may show increased susceptibility to higher levels of mitophagy. In order to test this hypothesis, a novel cancer therapy that leverages the mitochondrial dysfunction inherent in neoplastic cells to hyper-activate mitophagy and induce cell death using phenanthroline, an iron chelating drug, has been proposed. By disrupting genes frequently mutated in cancers using RNAi, it has been found that certain cancerous phenotypes that resulted from knockdowns in several key genes, including vps-34/VPS34, daf-16/FOXO3, atg-16.2/ATG16L1, cul-1/CUL1, and lin- 23/BTRC, were intrinsically more susceptible to iron chelating drugs and mitophagic activation than others. These results open a potential therapeutic window for a wide variety of cancers, ranging from colorectal cancers to breast and ovarian cancers. By harnessing the relationship between mitophagy and cancer, and through the identification and characterization of oncogenic transformations that are more sensitive to mitochondrial damage, a better understanding of appropriate cancer therapies is gained.