Insights into MYC biology through investigation of synthetic lethal interactions with MYC deregulation

MYC (or c-myc) is a bona fide "cancer driver" oncogene that is deregulated in up to 70% of human tumors. In addition to its well-characterized role as a transcription factor that can directly promote tumorigenic growth and proliferation, MYC has transcription-independent functions in vital cellular processes including DNA replication and protein synthesis, contributing to its complex biology. MYC expression, activity, and stability are highly regulated through multiple mechanisms. MYC deregulation triggers genome instability and oncogene-induced DNA replication stress, which are thought to be critical in promoting cancer via mechanisms that are still unclear. Because regulated MYC activity is essential for normal cell viability and MYC is a difficult protein to target pharmacologically, targeting genes or pathways that are essential to survive MYC deregulation offer an attractive alternative as a means to combat tumor cells with MYC deregulation. To this end, we conducted a genome-wide synthetic lethal shRNA screen in MCF10A breast epithelial cells stably expressing an inducible MYCER transgene. We identified and validated FBXW7 as a high-confidence synthetic lethal (MYC-SL) candid