Manipulating MAPK/c-Myc axis to overcome chemoresistance in CRC

Comprehensive genomic profiling is expected to revolutionize cancer therapy. Recent advances in DNA sequencing technologies provide unprecedented capacity to comprehensively identify the alterations, genes and pathways involved in the tumorigenic process, raising the hope that targeted therapies against the drivers of cancer can be extended from a few successful examples to a broader personalized medicine strategy. Colorectal cancer (CRC) poses a formidable challenge in the form of molecular heterogeneity with involvement of several cancer-related pathways and molecular changes unique to an individual's tumor. Recent discoveries have unveiled an impressive list of the RAS/RAF/MEK/ERK and PI3K/AKT pathway inhibitors, offering a new treatment paradigm for cancer patients. However, despite the initial promise, in 2018 only 15.4% of 610,000 patients with metastatic cancer were eligible for an FDA-approved, genome-guided drug, and just 6.6% of these patients likely benefited, also many patients relapse after a couple of years on the drugs, specially in CRC. The occurrence of chemoresistance is responsible for the limited success of various drugs. Indeed, blocking one pathway, such as RAS, is likely to induce only a cytostatic effect, while inhibiting a crosstalk resistance pathway should induce chemosensitivity and a final cytotoxic effect. These considerations highlight the relevance of molecular profiling and preclinical investigation in order to establish new therapeutic approaches based on the use of specific drugs targeted against the crucial drivers of cancer-related pathways. Indeed, a paradigm of this view is represented by the p38 MAPK, which is a central node between the Wnt, ERK, AMPK and PI3K cascades. In this work we tested p38α inhibitors in combination with molecularly-targeted drugs and chemotherapeutic agents in CRC xenografted nude mice and the AOM/DSS colitis-associated carcinoma preclinical model. To this aim, animals were treated with p38 inhibitor alone or in combination with the orally administrable MEK1 inhibitor PD0325901, the BRAF inhibitor Sorafenib or the chemotherapeutic agent Cisplatin. The combined use of p38α inhibitor with the indicated compounds significantly reduced tumor growth by inducing cytotoxic effect which is mediated by the apoptotic mechanism, the best method to kill cancer cells. Besides, we show that concomitant inhibition of the p38α and MEK/ERK pathways significantly increases the survival of APCMin/+ mice in which tumorigenesis is driven by c-Myc deregulation. Since c-Myc is able to activate cancer stem cells expression profile, which can be considered responsible for chemoresistance mechanism, it becomes clear that found a method to neutralized c-Myc can be the best way to overcome chemoresistance. Moreover we found that p38α and ERK collaborate in c-Myc stabilization by inhibiting its proteasomal degradation in CRC cell lines. We confirmed these results by using Ralimetinib (p38 inhibitor) and Trametinib (MEK inhibitor), which are currently in clinical trials for cancer and inflammatory disease. These data validate that combined inhibition of p38α and ERK pathway or the association with chemotherapy could be a promising approach to overcome chemoresistance in CRC.