Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Abstract

MYC is a master transcriptional regulator that controls almost all cellular processes. Over the last several decades, researchers have strived to define the context-dependent transcriptional gene programs that are controlled by MYC, as well as the mechanisms that regulate MYC function, in an effort to better understand the contribution of this oncoprotein to cancer progression. There are a wealth of data indicating that deregulation of MYC activity occurs in a large number of cancers and significantly contributes to disease progression, metastatic potential, and therapeutic resistance. Although the therapeutic targeting of MYC in cancer is highly desirable, there remain substantial structural and functional challenges that have impeded direct MYC-targeted drug development and efficacy. While efforts to drug the 'undruggable' may seem futile given these challenges and considering the broad reach of MYC, significant strides have been made to identify points of regulation that can be exploited for therapeutic purposes. These include targeting the deregulation of MYC transcription in cancer through small-molecule inhibitors that induce epigenetic silencing or that regulate the G-quadruplex structures within the MYC promoter. Alternatively, compounds that disrupt the DNA-binding activities of MYC have been the long-standing focus of many research groups, since this method would prevent downstream MYC oncogenic activities regardless of upstream alterations. Finally, proteins involved in the post-translational regulation of MYC have been identified as important surrogate targets to reduce MYC activity downstream of aberrant cell stimulatory signals. Given the complex regulation of the MYC signaling pathway, a combination of these approaches may provide the most durable response, but this has yet to be shown. Here, we provide a comprehensive overview of the different therapeutic strategies being employed to target oncogenic MYC function, with a focus on post-translational mechanisms.

MYC as a Multifaceted Regulator of Tumor Microenvironment Leading to Metastasis

“…Because of the ability to recruit stromal and infiltrating immune cells to promote invasive growth, MYC could also be called “the master regulator of tumor microenvironment”. Although MYC is a highly desirable target for anti-cancer drug development, there has been a lot of challenges that have held back the development of drugs directly targeting MYC [ 250 , 251 ]. However, there are already reported studies successful inhibiting MYC in tumor-associated macrophages, demonstrating that a better understanding of the role of MYC in the tumor microenvironment and metastasis could represent an effective way to successfully target MYC in cancer [ 30 , 252 ].…”

DNA folds threaten genetic stability and can be leveraged for chemotherapy

“…oncogene expression modulation for promoter G4s; telomere stability for telomeric G4s). 190,192,269 209,212,214,215 Name Family 216,217 And yet, G4 formation is intimately linked to all DNA transactions, favoured by the transient formation of ssDNA during DNA-replication and DNA-to-RNA transcription, when the B-helix is split apart and the single strands are subjected to negative supercoiling, in which helical tension is theorised to cause the DNA to curl like a twisted string. Whilst transactions induce their formation, G4s can physically impede these two processes, stopping or stalling the advancing polymerase, triggering DNA damage and activating DDR mechanisms.…”

Insights about MYC and Apoptosis in B-Lymphomagenesis: An Update from Murine Models

“…MBIII–IV motifs of MYC are pivotal for the roles of MYC in apoptosis and in its protein turnover. Another MYC key domain is represented by the bHLHZ motif that is required for the interaction between MYC and MAX, essential for DNA binding [ 14 ].…”