PO-006 The MAPK/c-Myc axis in CRC: new pathogenic mechanisms and therapeutic approaches

Abstract

Introduction c-Myc plays a central role in cellular proliferation, differentiation, and apoptosis. Therefore its deregulation represents a powerful trigger of tumorigenesis, particularly in colorectal cancer (CRC). It has been shown that the MEK/ERK pathway phosphorylates c-Myc on serine 62, which stabilises c-Myc by preventing ubiquitin/proteasomal degradation. We recently reported that MEK/ERK inhibition is counteracted by over-activation of p38α MAPK. Here, we identified cellular mechanisms that lead to c-Myc deregulation, which is a crucial issue for improving CRC treatment and survival. Material and methods The cross-talk between p38α and ERK was assessed in CRC cell lines and in APC Min/+ mice, a murine model of familial adenomatous polyposis. To this aim, animals were treated with the p38α inhibitor 4-(4-Fluorophenyl)−2-(4-hydroxyphenyl)−5-(4-pyridyl)−1H-imidazole (SB202190) alone or in combination with the MEK1 inhibitor N-[(2R)−2,3-Dihydroxypropoxy]−3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (PD0325901). In order to evaluate the role of p38α and ERK in c-Myc regulation, we used pharmacological inhibitors of these two kinases alone or in combination with inhibitors of the transcriptional mechanism, translational process and proteasome in CRC cell lines. Moreover, the function of p38α and ERK in Myc stabilisation was assessed by genetic ablation. Results and discussions Here we show that concomitant inhibition of the p38α and MEK/ERK pathways significantly increases the survival of APC Min/+ mice in which tumorigenesis is driven by c-Myc deregulation. Genetic ablation of p38α and ERK revealed that these two MAPKs do not regulate c-Myc expression, nor do they affect c-Myc protein translational process. We found that p38α and ERK collaborate in c-Myc stabilisation by inhibiting its proteasomal degradation in CRC cell lines. These results were also confirmed by using the p38α and ERK pharmacological inhibitors LY2228820 (Ralimetinib) and GSK1120212 (Mekinist), respectively, which are currently in clinical trials for inflammatory diseases and cancer. Conclusion Since c-MYC supports the processes required for normal growth and homeostasis, its ablation is less attractive than modulation of its expression or function. Our results confirmed the essential role of the MAPK/c-Myc axis in intestinal tumorigenesis regulation, suggesting MAPK manipulation as a potential therapeutic approach to counteract c-Myc dependent carcinogenesis.