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Review
. 2019 Oct 22;11(10):1618.
doi: 10.3390/cancers11101618.

A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer

Cornelia Braicu  1 , Mihail Buse  2 , Constantin Busuioc  3 , Rares Drula  4 , Diana Gulei  5 , Lajos Raduly  4 , Alexandru Rusu  6 , Alexandru Irimie  7   8 , Atanas G Atanasov  9   10   11 , Ondrej Slaby  12   13 , Calin Ionescu  14   15 , Ioana Berindan-Neagoe  16   17   18
Affiliations
Review

A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer

Cornelia Braicu et al. Cancers (Basel). .

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.

Keywords: MAPK; cancer; drug resistance; molecular mechanisms.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Parallel outline of several physiological roles of the TGFβ/p38, mitogen-activated protein kinase (MAPK), and P13k/AKT/mTOR signaling pathways. The p38 mitogen-activated kinase can be activated following upstream cytokine stimulation of the TGFβ pathway, which can subsequently activate TP53 in normal physiological conditions. TGFβ activation of p38 is not dependent on canonical SMAD signaling, but rather on the TAB/TAK1 complex and the MKK3/6 mitogen-activated protein kinase kinases. The canonical MAPK kinase pathway initiates with an extracellular stimulus in the form of growth factors (GFs) that bind and activate receptor tyrosine kinases (RTKs) on the cell membrane. Downstream activation of RAS, RAF and MEK in that order converge in the activation of the ERK1/2 transcription factor activator. The P13K/AKT/mTOR cascade can also be activated via RTKs and RAS, and its main implications are related to metabolic signaling and protein synthesis that sustain cell growth. TGFβ: transforming growth factor beta 1; p38: p38 kinase; P13k: phosphoinositide-3-kinase; AKT: v-akt murine thymoma viral oncogene homolog 1; mTOR: mechanistic target of rapamycin kinase; TAB: TGF-beta activated kinase 1 binding protein 2; TAK1: TGF-beta activated kinase 1; MKK3/6: mitogen-activated protein kinase kinase 3; RAS: small G-protein; RAF: Raf oncogene; MEK: MAP kinse-ERK kinase; RTKs: Receptor tyrosine kinases.
Figure 2
Figure 2
Mitogen-activated protein kinase (MAPK) inhibitor efficiency based on mutational status—cause of resistance and weak spots. Treatment resistance is a reoccurring problem in the case of MAPK pathway inhibitors. The post-treatment acquirement or selection of tumor cells with new mutations renders the treatment useless. In the case of KRAS, BRAF, and MEK inhibitors, mutations in any of these two components can determine therapeutic resistance and relapse. Targeting ERK can become a true Achilles heel in treating cancers with MAPK signaling alterations, as ERK inhibitors target specifically downstream of the signaling cascade, with no regard of the mutational status of the upstream components (e.g., KRAS and BRAF) (KRAS: Kirsten rat sarcoma viral oncogene homolog; BRAF: B-Raf proto-oncogene serine/threonine kinase; ERK:extracellular regulated MAP kinase).
Figure 3
Figure 3
Targeted components of the MAPK and AKT signaling cascades by small-molecule inhibitors in cancer. Effective targeting of the pathway intermediates is an efficient tactic in the case of constitutively activated signaling cascades, such as the MAPK pathway in cancer. Successful inhibition of a step in the cascade impairs the downstream progression of the pathway and its overall aberrant function. Combinations of inhibitors or multi-targeting molecules are being investigated, as they might provide more efficient manipulation of the entire signaling pathway. (MAPK: mitogen-activated protein kinase AKT: v-akt murine thymoma viral oncogene homolog 1).
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