Heme overdrive rewires pan-cancer cell metabolism

Abstract

A novel method of treating cancer is presented. In cancer cells, genes are not needed to biosynthesize either early precursor (e.g., ALA, porphobilinogen) or heme end products for survival. Rather, cancer cells require genes for accumulation of heme intermediates (e.g., PPIX) for survival and they only require genes encoding HMBS (3step), UROS (4step), UROD (5step) and CPOX (6step) for survival. This cancer metabolic rewiring process is termed 'heme overdrive'. This dependence on genes encoding these enzymes is present in all cancers and absent in all normal cells, thus heme overdrive provides an ideal cancer therapeutic target in terms of effectiveness, low toxicity, and applicability against a broad range of cancers. By inducing accumulation of heme precursor porphyrin metabolites, such as PPIX, and subsequently treating with a ferroptosis inducing compound, cancer cell death occurs with low to no toxicity in normal cells.