Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics

Brett D McKInnon, Brett McKinnon, Vida Kocbek, Kocbek V, Kostantinos Nirgianakis, Konstantinos Nirgianakis, Nirgianakis K, Nick A. Bersinger, Bersinger NA, Mueller MD, Michael D. Mueller
Human Reproduction Update · 2016 · vol. 22(3) , pp. 382–403 · doi:10.1093/humupd/dmv060 · PMID:26740585 · W2284803191
Review OA: bronze CC0 ⤵ 146 in-corpus citations
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Endometriosis lesions display constitutive activation of three key kinase pathways (NFκB, MAPK, PI3K/AKT/mTOR) that are potential targets for non-hormonal therapeutics, though clinical efficacy and side effects require further improvement.

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Abstract

BACKGROUND: Endometriosis, the growth of endometrial tissue outside the uterine cavity, is associated with chronic pelvic pain, subfertility and an increased risk of ovarian cancer. Current treatments include the surgical removal of the lesions or the induction of a hypoestrogenic state. However, a reappearance of the lesion after surgery is common and a hypoestrogenic state is less than optimal for women of reproductive age. Additional approaches are required. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, oxidative stress and iron. This environment influences cell survival through the binding of membrane receptors and a subsequent cascading activation of intracellular kinases that stimulate a cellular response. Many of these kinase signalling pathways are constitutively activated in endometriosis. These pathways are being investigated as therapeutic targets in other diseases and thus may also represent a target for endometriosis treatment. METHODS: To identify relevant English language studies published up to 2015 on kinase signalling pathways in endometriosis, we searched the Pubmed database using the following search terms in various combinations; 'endometriosis', 'inflammation', 'oxidative stress', 'iron', 'kinase', 'NF kappa', 'mTOR', 'MAPK' 'p38', 'JNK', 'ERK' 'estrogen' and progesterone'. Further citing references were identified using the Scopus database and finally current clinical trials were searched on the clinicaltrials.gov trial registry. RESULTS: The current literature on intracellular kinases activated by the endometriotic environment can be summarized into three main pathways that could be targeted for treatments: the canonical IKKβ/NFκB pathway, the MAPK pathways (ERK1/2, p38 and JNK) and the PI3K/AKT/mTOR pathway. A number of pharmaceutical compounds that target these pathways have been successfully trialled in in vitro and animal models of endometriosis, although they have not yet proceeded to clinical trials. The current generation of kinase inhibitors carry a potential for adverse side effects. CONCLUSIONS: Kinase signalling pathways represent viable targets for endometriosis treatment. At present, however, further improvements in clinical efficacy and the profile of adverse effects are required before these compounds can be useful for long-term endometriosis treatment. A better understanding of the molecular activity of these kinases, including the specific extracellular compounds that lead to their activation in endometriotic cells specifically should facilitate their improvement and could potentially lead to new, non-hormonal treatments of endometriosis.

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Condition tags

endometriosischronic_pelvic_pain

MeSH descriptors

Endometriosis Phosphatidylinositol 3-Kinases Animals Animals Endometriosis Endometriosis Endometriosis Estrogens Estrogens Estrogens Female Female Humans Humans I-kappa B Kinase I-kappa B Kinase I-kappa B Kinase Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinase Kinases

Citation neighborhood (2-hop)

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. Outer rings show 2-hop neighbours — papers reached through the immediate citers/citees. [ collapse to 1-hop ]

References (100)

Cited by (50)

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europepmc
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