Abstract
The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both the homeostatic and the pathologic conduct of MAPK signaling; however, there is still much to be deciphered in terms of regulation and action models in both preclinical and clinical research. MAPK has implications in the response to cancer therapy, particularly the activation of the compensatory pathways in response to experimental MAPK inhibition. The present paper discusses new insights into MAPK as a complex cell signaling pathway with roles in the sustenance of cellular normal conduit, response to cancer therapy, and activation of compensatory pathways. Unfortunately, most MAPK inhibitors trigger resistance due to the activation of compensatory feed-back loops in tumor cells and tumor microenvironment components. Therefore, novel combinatorial therapies have to be implemented for cancer management in order to restrict the possibility of alternative pathway activation, as a perspective for developing novel therapies based on integration in translational studies.
Highlights
Cancer stands as one of the greatest challenges to global health
This study revealed a novel function for ARAF, which, once in dimer form, activates the mitogen-activated protein kinase (MAPK) cascade with an impact on sustaining lung cancer cell invasion [41]
For the treatment of patients with advanced solid tumors, where the therapy was proven to be efficient even in NRAS- and BRAF V600-mutated tumors [30]. Another promising ERK1/2 inhibitor is ulixertinib (BVD-523, VRT752271); this compound has a significant anti-tumoral effect in several cell lines, including those having mutations in the MAPK signaling pathways [121]. This is of particular interest given the recently published review that discussed ERK1/2 regulatory involvement in terms of cellular stress-induced senescence and how this mechanism has the therapeutic potential for regulating cancer [122]
Summary
Cornelia Braicu 1,† , Mihail Buse 2,† , Constantin Busuioc 1,† , Rares Drula 1 , Diana Gulei 2 , Lajos Raduly 1 , Alexandru Rusu 3 , Alexandru Irimie 4,5 , Atanas G. Atanasov 6,7,8 , Ondrej Slaby 9,10 , Calin Ionescu 11,12, * and Ioana Berindan-Neagoe 1,2,13. Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu. Dr Ion. Co-first authors of this study. Received: 19 September 2019; Accepted: 16 October 2019; Published: 22 October 2019
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