Synthetic Lethal Screens as a Means to Understand and Treat MYC-Driven Cancers

Abstract

While therapeutics against MYC could potentially be employed against a wide range of human cancers, MYC targeted therapies have proven difficult to develop. The convergence of breakthroughs in human genomics and in gene silencing using RNA interference (RNAi), have recently allowed functional interrogation of the genome and systematic identification of synthetic lethal interactions with hyper-active MYC. Here, we focus on the pathways that have emerged through RNAi screens and present evidence that a subset of genes exhibiting synthetic lethality with MYC are significantly interconnected and linked to chromatin, and transcriptional processes, as well as to DNA repair and cell-cycle checkpoints. Other synthetic lethal interactions with MYC point to novel pathways and potentially broaden the repertoire of targeted therapies. The elucidation of MYC synthetic lethal interactions is still in its infancy and how these interactions may be influenced by tissue specific programs and by concurrent genetic change will require further investigation. Nevertheless, we predict that these studies may lead the way to novel therapeutic approaches and new insights into the role of MYC in cancer.

An Overview of MYC and Its Interactome

“…For reviews on the role of MYC family genes in neoplasia, see Huang and Weiss (2013), Kuzyk and Mai (2014), Roussel and Robinson (2013), Gabay et al (2014), and Schmitz et al (2014). Therapeutic approaches to cancer through inhibition of MYC activity are reviewed in Bradner (2014), Gabay et al (2014), and Cermelli et al (2014).…”

Focal adhesion kinase activation limits efficacy of Dasatinib in c‐Myc driven hepatocellular carcinoma

“…Despite the key role of c‐Myc in tumorigenesis, its suppression by direct inhibition is difficult to achieve . In recent years, significant efforts have been devoted to screen for genetic or metabolic events that may lead to synthetic lethality for c‐Myc . In a recent study, using chemical‐genetic interaction mapping technology, it was uncovered that c‐Myc overexpressing cells are highly sensitive to Dasatinib .…”

Building high-resolution synthetic lethal networks: a ‘Google map’ of the cancer cell

“…Recent genome-wide approaches that aim to identify NGIs directly in human cancer cells Genomic tools of genetic manipulation The advent of RNAi [mediated by siRNA and short hairpin RNA (shRNA), and the recent class of RNA guided endonucleases single guide RNA (sgRNA)] has provided the specificity needed to perform systematic functional genomics screens in human cancer cells [11,[51][52][53][54][55][56][57][58]. While the siRNA and shRNA reagents function at the mRNA level, sgRNAs function at the genome level to manipulate gene functionality ( Figure 2).…”