Taking on Challenging Targets: Making MYC Druggable

Abstract

The transcription factor proto-oncogene c-MYC (hereafter MYC) was first identified more than 3 decades ago and has since been found deregulated in a wide variety of the most aggressive human malignancies. As a pleiotropic transcription factor, MYC directly or indirectly controls expression of hundreds of coding and noncoding genes, which affect cell cycle entry, proliferation, differentiation, metabolism, and death/survival decisions of normal and cancer cells. Tumors with elevated MYC expression often exhibit highly proliferative, aggressive phenotypes, and elevated MYC expression has been correlated with diminished disease-free survival for a variety of human cancers. The use of MYC overexpression or MYC-dependent transcriptional gene signatures as clinical biomarkers is currently being investigated. Furthermore, preclinical animal and cell-based model systems have been extensively utilized in an effort to uncover the mechanisms of MYC-dependent tumorigenesis and tumor maintenance. Despite our ever-growing understanding of MYC biology, currently no targeted therapeutic strategy is clinically available to treat tumors that have acquired elevated MYC expression. This article summarizes the progresses being made to discover and implement new therapies to kill MYC over-expressing tumors—a target that was once deemed undruggable.KEY POINTSDespite MYC's widespread amplification or increased expression in many cancer types, no clinically approved therapies that target it currently exist.The major obstacle in directly inhibiting MYC function is that it is an essential pleiotropic transcription factor that controls the expression of hundreds of genes.Several small molecule nonkinase inhibitors that can modulate MYC transcriptional activity are currently under preclinical development and evaluation.MYC-driven tumors are dependent on various downstream signaling pathways, including those that regulate the cell cycle, stress-responses, and metabolic pathways, increasing the possibilities of targeting these pathways.Synthetic lethal approaches that target essential signaling pathways downstream of MYC activity—such as cell cycle and metabolism—can provide new therapeutic opportunities to selectively kill MYC-driven tumors.