Conjunctival Melanoma Targeted Therapy: MAPK and PI3K/mTOR Pathways Inhibition
| Autor: | Ezziat Sakina, Leonidas Zografos, Gürkan Kaya, Rosanna Pescini Gobert, Alexandre Moulin, Donata Rimoldi, Ikram El Zaoui, Serge Leyvraz, Carlo Rivolta, Michael Nicolas, Nicola Bedoni, Maya Bucher, Ann Schalenbourg, Nicolo Riggi |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Neuroblastoma RAS viral oncogene homolog MAPK/ERK pathway Melanoma/drug therapy/enzymology/pathology Protein Kinase Inhibitors/therapeutic use Fluorescent Antibody Technique Pyrimidinones/therapeutic use Phosphatidylinositol 3-Kinases 0302 clinical medicine Tumor Cells Cultured 80 and over Molecular Targeted Therapy Pyridones/therapeutic use Fluorescent Antibody Technique Indirect skin and connective tissue diseases Vemurafenib Melanoma Quinolines/therapeutic use Indazoles/therapeutic use Aged 80 and over ddc:616 Trametinib Sulfonamides TOR Serine-Threonine Kinases/antagonists & inhibitors Cultured Blotting TOR Serine-Threonine Kinases Imidazoles Middle Aged Tumor Cells 030220 oncology & carcinogenesis Quinolines Female Mitogen-Activated Protein Kinases Western medicine.drug Proto-Oncogene Proteins B-raf Adult Benzimidazoles/therapeutic use Indirect Indazoles Pyridones Blotting Western Antineoplastic Agents Conjunctival Neoplasms Imidazoles/therapeutic use Pyrimidinones Phosphatidylinositol 3-Kinases/drug effects 03 medical and health sciences Proto-Oncogene Proteins B-raf/genetics medicine Humans Protein Kinase Inhibitors neoplasms PI3K/AKT/mTOR pathway Aged business.industry Antineoplastic Agents/therapeutic use Conjunctival Neoplasms/drug therapy/enzymology/pathology Mitogen-Activated Protein Kinases/antagonists & inhibitors Sulfonamides/therapeutic use medicine.disease 030104 developmental biology Cancer research Selumetinib Benzimidazoles business Conjunctival Melanoma |
| Zdroj: | Investigative ophthalmology & visual science, vol. 60, no. 7, pp. 2764-2772 Investigative Ophthalmology & Visual Science, Vol. 60, No 7 (2019) pp. 2764-2772 |
| ISSN: | 1552-5783 0146-0404 |
| DOI: | 10.1167/iovs.18-26508 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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