A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer

Abstract

The knowledge accumulating on the occurrence and mechanisms of the activation of oncogenes in human neoplasia necessitates an increasingly detailed understanding of their systemic interactions. None of the known oncogenic drivers work in isolation from the other oncogenic pathways. The cooperation between these pathways is an indispensable element of a multistep carcinogenesis, which apart from inactivation of tumor suppressors, always includes the activation of two or more proto-oncogenes. In this review we focus on representative examples of the interaction of major oncogenic drivers with one another. The drivers are selected according to the following criteria: (1) the highest frequency of known activation in human neoplasia (by mutations or otherwise), (2) activation in a wide range of neoplasia types (universality) and (3) as a part of a distinguishable pathway, (4) being a known cause of phenotypic addiction of neoplastic cells and thus a promising therapeutic target. Each of these universal oncogenic factors—mutant p53, KRAS and CMYC proteins, telomerase ribonucleoprotein, proteasome machinery, HSP molecular chaperones, NF-κB and WNT pathways, AP-1 and YAP/TAZ transcription factors and non-coding RNAs—has a vast network of molecular interrelations and common partners. Understanding this network allows for the hunt for novel therapeutic targets and protocols to counteract drug resistance in a clinical neoplasia treatment.

Pairwise and higher-order epistatic effects among somatic cancer mutations across oncogenesis

“…KRAS and TP53 have been suggested to play a key role in the initial stages of the somatic evolution of many lung adenocarcinomas [32–34]. Our analysis provided a result consistent with these findings: KRAS is subject to a synergistic epistatic effect on its selection in the context of TP53 mutations.…”

“…Additionally, LRP1B appears to cooperate with TP53 to induce a large selection for mutant KRAS as a driver of lung adenocarcinoma [3]. and TP53 have been suggested to play a role in lung adenocarcinoma initiation [22]. KRAS mutations are consistently revealed by sequencing of all grades [23], and because of identification of copy number gains that enable estimation of the relative timing of somatic alterations [24].…”

The Gain-of-Function p53 R248W Mutant Promotes Migration by STAT3 Deregulation in Human Pancreatic Cancer Cells

“…Regarding co-factors, it is conceivable that the mutp53 protein also adds p53-specific coactivators into this illegitimate mix, and/or that the canonical coactivator specific for the partnering transcription factor might get displaced. Thus, interplay networks of mutp53 with co-regulation of various tumor drivers is essential for GOF-mediated cancer progression (4,6,24,60,63). This concept could explain why the mutp53 status or the status of STAT3 phosphorylation alone is not yet a determinant for migration but depends on the specific missense mutation, resulting in specific mutp53-pSTAT3 complexes with mutp53 variant-specific transcriptional cofactors.…”

Molecular Targeting of the Most Functionally Complex Gene in Precision Oncology: p53

“…Perhaps one of the most interesting possibilities is cooperative regulation by c-Myc and RAS; both of which are frequently mutated and activated in many cancers [ 82 , 196 , 197 ]. RAS and c-Myc are intricately linked, with aberrant RAS signaling resulting in increased c-Myc protein stability [ 198 ]. c-Myc directly binds to and positively regulates the p53 promoter [ 80 ].…”

“…Therefore, a loss of p53 could result in BTG2 loss, which causes RAS activity to increase, leading to increased stability of c-Myc and transcriptional activation of c-Myc regulated genes, including p53. RAS has also been demonstrated to activate NF-κB, which in addition to increasing c-Myc expression [ 198 ] also directly binds to the p53 promoter and induces its expression ( Figure 3 A). Oncogenic signaling through these proteins would remain active in the event of p53 loss, resulting in persistent activation of the p53 promoter.…”