Role of the protein kinase BRAF in the pathogenesis of endometriosis

Piétro Santulli, Pietro Santulli, Louis Marcellin, Sandrine Chouzenoux, Veronique Boulard, Pierre‐Alexandre Just, Pierre-Alexandre Just, Carole Nicco, Christiane Chéreau, Christiane Chereau, Claudia Tosti, Charles Chapron, Frédéric Batteux
Expert opinion on therapeutic targets · 2016 · vol. 20(8) , pp. 1017–1029 · doi:10.1080/14728222.2016.1180367 · PMID:27087167 · W2341081989
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Vemurafenib (PLX4032) inhibited BRAF and reduced endometriotic cell proliferation, apoptosis, and inflammation in vitro, and decreased lesion size in a mouse model.

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Abstract

OBJECTIVE: Mitogen-activated protein kinases (MAPKs) are involved in the proliferation and survival of endometriotic lesions. Vemurafenib (PLX4032) is a novel protein kinase inhibitor that targets BRAF, a member of the MAPK pathway. The present study tested the in vitro and in vivo effects of PLX4032 on endometriotic cells. RESEARCH DESIGN AND METHODS: We conducted a laboratory study in a tertiary-care university hospital from January 2013 to September 2013. We enrolled a cohort of 40 patients: 20 with histologically proven endometriosis and 20 unaffected women. A thorough surgical examination of the abdominopelvic cavity was performed on all of the study participants. Ex vivo stromal and epithelial cells were extracted from endometrial and endometriotic biopsies from both sets of patients. Proliferation, apoptosis, pERK/ERK ratio, cell cycle regulation (Cyclin D1 and CDK4) and inflammation (PTGS2) were explored with and without PLX4032 treatment. Human endometriotic lesions were implanted into 40 nude mice that were separated into two groups according to PLX4032 or vehicle treatment, which they received for four weeks, before sacrifice and histological examination. RESULTS: Treating endometriotic cells with PLX4032 abrogated the phosphorylation of ERK, significantly reducing the pERK/ERK ratio in both epithelial and stromal cells from endometriotic women compared to the controls (p < 0.05). In addition, treatment with PLX4032 significantly decreased proliferation in both stromal and epithelial cells with a concomitant decrease in Cyclin D1/CDK4 complex and PTGS2 levels. Using a murine model of endometriosis, we observed that PLX4032-treated mice displayed a significant decrease in implant volume compared to the initial size; a slight, but non-significant, increase in size was observed in the vehicle-treated mice. CONCLUSION: Our data suggest that MAPKs and BRAF are involved in the pathogenesis of endometriosis. PLX4032-induced inhibition of BRAF controlled endometriotic growth, both in vitro and in vivo, and could constitute a promising target for the treatment of endometriosis.

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Condition tags

endometriosis

MeSH descriptors

Antineoplastic Agents Endometriosis Indoles Proto-Oncogene Proteins B-raf Sulfonamides Adult Animals Antineoplastic Agents Apoptosis Apoptosis Case-Control Studies Cell Proliferation Cell Proliferation Disease Models, Animal Endometriosis Endometriosis Epithelial Cells Epithelial Cells Female Humans

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