Targeting of the MAPK and AKT pathways in conjunctival melanoma shows potential synergy
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Jinfeng Cao1,2, Renier C. Heijkants3, Aart G. Jochemsen3, Mehmet Dogrusöz1, Mark J. de Lange1, Pieter A. van der Velden1, Sjoerd H. van der Burg5, Martine J. Jager1,* and Robert M. Verdijk4,*
1Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
2Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China
3Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
4Department of Pathology, Section Ophthalmic Pathology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
5Department of Clinical Oncology, LUMC, Leiden, The Netherlands
*Both authors have shared senior authorship
Robert M. Verdijk, email: firstname.lastname@example.org
Keywords: conjunctival melanoma, MAPK, AKT, nevus, kinase inhibitor
Received: December 28, 2015 Accepted: June 09, 2016 Published: July 22, 2016
Purpose: Conjunctival melanoma (CM) is a rare but lethal form of cancer. Similar to cutaneous melanoma, CM frequently carries activating mutations in BRAF and NRAS. We studied whether CM as well as conjunctival benign and premalignant melanocytic lesions express targets in the mitogen-activated protein kinase (MAPK) and AKT pathways, and whether specific inhibitors can suppress CM growth in vitro.
Methods: 131 conjunctival lesions obtained from 129 patients were collected. The presence of BRAF V600E mutation and expression of phosphorylated (p)-ERK and p-AKT were assessed by immunohistochemistry. We studied cell proliferation, phosphorylation, cell cycling and apoptosis in three CM cell lines using two BRAF inhibitors (Vemurafenib and Dabrafenib), a MEK inhibitor (MEK162) and an AKT inhibitor (MK2206).
Results: The BRAF V600E mutation was present in 19% of nevi and 26% of melanomas, but not in primary acquired melanosis (PAM). Nuclear and cytoplasmic p-ERK and p-AKT were expressed in all conjunctival lesions. Both BRAF inhibitors suppressed growth of both BRAF mutant CM cell lines, but only one induced cell death. MEK162 and MK2206 inhibited proliferation of CM cells in a dose-dependent manner, and the combination of these two drugs led to synergistic growth inhibition and cell death in all CM cell lines.
Conclusion: ERK and AKT are constitutively activated in conjunctival nevi, PAM and melanoma. While BRAF inhibitors prohibited cell growth, they were not always cytotoxic. Combining MEK and AKT inhibitors led to more growth inhibition and cell death in CM cells. The combination may benefit patients suffering from metastatic conjunctival melanoma.
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