Targeting oncogenic Myc as a strategy for cancer treatment

Abstract

The MYC family oncogene is deregulated in >50% of human cancers, and this deregulation is frequently associated with poor prognosis and unfavorable patient survival. Myc has a central role in almost every aspect of the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. Although Myc inhibition would be a powerful approach for the treatment of many types of cancers, direct targeting of Myc has been a challenge for decades owing to its "undruggable" protein structure. Hence, alternatives to Myc blockade have been widely explored to achieve desirable anti-tumor effects, including Myc/Max complex disruption, MYC transcription and/or translation inhibition, and Myc destabilization as well as the synthetic lethality associated with Myc overexpression. In this review, we summarize the latest advances in targeting oncogenic Myc, particularly for cancer therapeutic purposes.

Fig. 1

Myc regulates a spectrum of cellular functions. Myc regulates a large number of protein-coding or non-coding genes that are involved in distinct cellular functions, including cell cycle, protein biogenesis, cell adhesion, metabolism, signal transduction, transcription, and translation, among others

Fig. 2

Transcriptional activation of target genes by Myc family members. a protein structure of Myc family members. The N terminus of Myc comprises a transactivation domain (TAD) and three highly conserved elements, known as Myc boxes 1–3. Myc box 1 (MB1) possesses a phosphodegron, which is targeted by the ubiquitin E3 ligase FBW7. MB2 is required for all the known functions of Myc and recruits a histone acetyltransferase (HAT) complex, MB3 regulates Myc protein stability and transcriptional activities. The C-terminal domain contains a basic-region /helix-loop-helix/leucine-zipper (BR/HLH/LZ) motif that is necessary for DNA–protein interactions. Max, the partner of Myc, binds with Myc through the C-terminal BR/HLH/LZ motif. b Myc functions as a transcription factor. Upon binding to CACGTG (E-box), the Myc–Max dimeric complex recruits chromatin-modifying complexes, including GCN5, TIP60, TIP48, and TRRAP, leading to transcriptional activation. GCN5 and TIP60 are histone acetyltransferases; TIP48 is an ATP-binding protein, TRRAP transactivation/transformation-associated protein. c Myc functions as a transcriptional signal amplifier. In this model, Myc binding is not E-box dependent. Myc accumulates in the promoter and enhancer region of all active genes and causes transcriptional signal amplification

Fig. 3

Various strategies to target Myc. Inhibitors of BRD4, CDK7, and CDK9 inhibit MYC expression at the transcriptional level. Inhibition of the PI3K/AKT/mTOR pathway blocks MYC translation, whereas USP7, AURKA, and PLK1 inhibitors destabilize Myc at the posttranslational level. 10058-F4 and Omomyc function to interrupt the Myc–Max dimeric complex. BRD4 bromodomain-containing 4, CDK7 cyclin-dependent kinase 7, CDK9 cyclin-dependent kinase 9, PLK1 polo-like kinases 1, PI3K/AKT/mTOR phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin

Fig. 4

Synthetic lethal interactions with Myc deregulation. Myc-mediated synthetic lethality has been observed with various targets, including CDK1, CHK1, and GLS. CDK1 cyclin-dependent kinase 1, CHK1 checkpoint kinase 1, GLS glutaminase