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.

Biozoon GmbH D 27572 Bremerhaven Germany

Central European Institute of Technology Masaryk University 601 77 Brno Czech Republic

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute 601 77 Brno Czech Republic

Department of Functional Genomics and Experimental Pathology The Oncology Institute Prof Dr Ion Chiricuta Republicii 34 Street 400015 Cluj Napoca Romania

Department of Pharmacognosy University of Vienna Althanstrasse 14 1090 Vienna Austria

Department of Surgery Iuliu Hatieganu University of Medicine and Pharmacy 23 Marinescu Street 40015 Cluj Napoca Romania

Department of Surgery The Oncology Institute Prof Dr Ion Chiricuta 40015 Cluj Napoca Romania

Department of Surgical Oncology and Gynecological Oncology Iuliu Hatieganu University of Medicine and Pharmacy 40015 Cluj Napoca Romania

Institute of Genetics and Animal Breeding of the Polish Academy of Sciences Jastrzebiec 05 552 Magdalenka Poland

Institute of Neurobiology Bulgarian Academy of Sciences 23 Acad G Bonchev str 1113 Sofia Bulgaria

MEDFUTURE Research Center for Advanced Medicine Iuliu Hatieganu University of Medicine and Pharmacy 23 Marinescu Street 40015 Cluj Napoca Romania

Research Center for Functional Genomics Biomedicine and Translational Medicine Iuliu Hatieganu University of Medicine and Pharmacy 23 Marinescu Street 40015 Cluj Napoca Romania

th Surgical Department Municipal Hospital 400139 Cluj Napoca Romania

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Phosphorylated and Phosphomimicking Variants May Differ-A Case Study of 14-3-3 Protein