A Novel Synthetic Lethal Approach to Target MYC-Driven Cancers

The MYC proto-oncogene family encompasses three related transcription factors (MYC, MYCL, and MYCN), which are master regulators of cellular programs orchestrating multiple hallmarks of cancer, including proliferation, metabolism, invasiveness, and immune surveillance. MYC activation is one of the most frequent alterations in cancer, induced by genetic, epigenetic, or posttranslational alterations of MYC itself, or of MYC-related proteins or pathways. Sun and colleagues found a unique function of the ratelimiting nucleotide synthesis enzyme CTP synthase 1 (CTPS1) in the survival of MYC-driven cancer cells. They further identified a novel synthetic lethal strategy to combat MYC-driven cancers by combining CTPS1 inhibitors with ataxia telangiectasia and Rad3- related protein inhibitors, which exploits the inherent vulnerability of MYC-driven tumors to nucleotide shortage and DNA replication stress. These findings open novel therapeutic avenues for targeting the traditionally "undruggable"MYC-driven cancers, which represent one of the highest unmet clinical needs in cancer.