Investigating Mechanisms of Mitochondrial Complex II Dependence in Cancer

Abstract

AbstractCancer cells are marked by dysregulated metabolism. Recently, it is increasingly appreciated that oxidative phosphorylation (OXPHOS) is upregulated in certain cancers and can even contribute to resistance to cancer therapies, nominating OXPHOS inhibition as a potential cancer therapeutic target. While a novel electron transport chain (ETC) complex I inhibitor yielded promising results in vitro and in vivo in particular genetic and lineage-dependent contexts, the inhibitor ultimately failed in a high profile clinical trial due to dose-limiting toxicities incurred by targeting a metabolic node that ultimately is fundamental in non-cancerous cells. However, complex III inhibitors are proceeding through clinical trials, indicating that inhibition of the ETC at these nodes can be a safe therapeutic option in the right contexts. Here, we sought to determine the landscape of ETC complex dependences across cancers. We observed general dependence on complex I across cell lines, while dependence on complexes II through V widely varied. In particular, hematological cancers exhibited heightened dependence on complex II. In order to determine what drives this dependence, we performed unbiased computational analyses connecting chemical and genetic inhibition of complex II to identify co-essential genes and pathway. These analyses identified de novo purine synthesis as a strong and unique correlate of sensitivity to complex II. Subsequent metabolomics and mechanistic studies found that complex II directly regulates purine levels and purine synthesis to maintain proliferation. We further linked the oxidation of glutamate, which is generated by rate-limiting glutamine-consuming steps in purine synthesis, as a necessary function of complex II. When complex II is inhibited, glutamate cannot be oxidized and causes negative feedback on glutamine to glutamate steps during purine synthesis to suppress the pathway. Together, these studies have identified an unexpected and fundamental role of complex II in regulating purine synthesis.