Abstract
Core regulatory circuitry refers to the network of lineage-specific transcription factors regulating expression of both their own coding genes, and that of other transcription factors. Such autoregulatory feedback loops coordinate the transcriptome and epigenome during development and cell fate decisions. This circuitry is hijacked during oncogenesis resulting in cancer cell fate being maintained by lineage-specific transcription factors. Major advances in functional genomics and chemical biology are paving the way for a new generation of cancer therapeutics aimed at disrupting this circuitry through both direct and indirect means. Here we review these critical advances in mechanistic understanding of transcription factor addiction in cancer and how the advent of proteolysis targeting chimeras and CRISPR screen assays are leading the way for a new paradigm in targeted cancer treatments.