Conjunctival Melanoma Targeted Therapy: MAPK and PI3K/mTOR Pathways Inhibition

El Zaoui, Ikram and Bucher, Maya and Rimoldi, Donata and Nicolas, Michael and Kaya, Gurkan and Pescini Gobert, Rosanna and Bedoni, Nicola and Schalenbourg, Ann and Sakina, Ezziat and Zografos, Leonidas and Leyvraz, Serge and Riggi, Nicolo and Rivolta, Carlo and Moulin, Alexandre P.. (2019) Conjunctival Melanoma Targeted Therapy: MAPK and PI3K/mTOR Pathways Inhibition. Investigative Ophthalmology & Visual Science, 60 (7). pp. 2764-2772.

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Official URL: https://edoc.unibas.ch/81676/

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To analyze the activity of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases/mechanistic target of rapamycin (PI3K/mTOR) pathways in benign and malignant conjunctival melanocytic proliferations and explore whether specific inhibitors can suppress growth of conjunctival melanoma (CJM) cells.; The presence of a BRAF V600E mutation and activation of ERK, MEK, S6, and AKT were assessed with immunohistochemistry in 35 conjunctival nevi and 31 melanomas. Three CJM cell lines were used: CRMM1, carrying the BRAF V600E mutation; CRMM2, harboring the NRAS Q61L mutation; and T1527A, with a BRAF G466E mutation. WST-1 assays were performed with a BRAF inhibitor (vemurafenib), two MEK inhibitors (trametinib, selumetinib), a PI3K inhibitor (pictilisib), and a dual PI3K/mTOR inhibitor (dactolisib). The phosphorylation of ERK, MEK, and S6 were tested with western blots and apoptosis with cleaved caspase-3 immunostaining.; A BRAF V600E mutation was detected in 42.6% of nevi and in 35.5% of CJM. MEK and ERK activation were higher in CJM, occurring in 62.9% and 45.7% of the nevi and 90.3% and 96.8% of the CJM, respectively. There was also a significant increase in S6 activation in CJM (90.3%) compared with the nevi (20%). CRMM1 was sensitive to trametinib and the PI3K inhibitors but only marginally to vemurafenib. CRMM2 was moderately sensitive to pictilisib, whereas T1527A was resistant to all drugs tested.; The MAPK pathway activity in CJM is increased, not only as a consequence of the BRAF V600E mutation. Targeted therapy may be useful for patients with CJM, especially those with activating BRAF mutations, whereas NRAS-mutated melanomas are relatively resistant.
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Association for Research in Vision and Ophthalmology
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:26 Feb 2021 11:13
Deposited On:26 Feb 2021 11:13

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