June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
MAPkinase and PI3K/mTOR pathways inhibition in conjunctival melanoma
Author Affiliations & Notes
  • Ikram El Zaoui El-Zaoui
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Michael Nicolas
    Department of Ophthalmology, University of Lausanne, Switzerland, ules-Gonin Eye Hospital, Lausanne, Switzerland
  • Rosanna Pescini Gobert
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Donata Rimoldi
    Ludwig Institute for Cancer Research, Lausanne, Switzerland
  • Serge Leyraz
    Department of Oncology, Lausanne, Switzerland
  • Carlo Rivolta
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Alexandre Moulin
    Department of Ophthalmology, University of Lausanne, Switzerland, ules-Gonin Eye Hospital, Lausanne, Switzerland
  • Footnotes
    Commercial Relationships   Ikram El-Zaoui, None; Michael Nicolas, None; Rosanna Pescini Gobert, None; Donata Rimoldi, None; Serge Leyraz, None; Carlo Rivolta, None; Alexandre Moulin, None
  • Footnotes
    Support  None in the Support field below
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 3346. doi:
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      Ikram El Zaoui El-Zaoui, Michael Nicolas, Rosanna Pescini Gobert, Donata Rimoldi, Serge Leyraz, Carlo Rivolta, Alexandre Moulin; MAPkinase and PI3K/mTOR pathways inhibition in conjunctival melanoma. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3346.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Evidence suggests that conjunctival and cutaneous melanoma partially share similar genetic alterations. Considering the presence of BRAF and NRAS mutations in conjunctival melanoma, we have previously demonstrated ex vivo a significant activation of the Mitogen-activated protein kinase (MAPK) and the Phosphoinositide 3 kinase (PI3K/mTOR) pathways in conjunctival melanoma compared to conjunctival naevi. We now explore the inhibition of these pathways in three conjunctival melanoma cell lines.

Methods : Three conjunctival melanoma cell lines were used: CRMM1, carrying the p.V600E mutation in BRAF, CRMM2, harboring the p.Q61L NRAS mutation, and T1527A, a conjunctival melanoma cell line with no mutations in these genes that was recently established by us. WST-1 assays were performed to assess cytotoxicity with a BRAF inhibitor (PLX032), two MEK inhibitors (AZD6244 and GSK1120212), PI3K inhibitor (GDC-0941) and a dual PI3K/mTOR inhibitor (BEZ235). Viability was determined by Tryptan blue assays. Phosphorylation of ERK, MEK and S6 was tested by western blots.

Results : CRMM1 cells were relatively more sensitive to all inhibitors than CRMM2. In addition, CRMM2 cells were also sensitive to the dual PI3K/mTOR inhibitors at low concentration (LC50 10 µM).T1527A cells showed little sensitivity to these treatments (LC50 >1 mM). Cytotoxicity was observed with all inhibitors at high concentrations for all cell lines. Furthermore, western blot experiments showed that all drugs inhibited the phosphorylation of their specific target proteins in a dose-dependent manner.

Conclusions : Our results confirm the sensitivity of conjunctival melanoma cell lines to selective inhibition of either the MAPK or the PI3K/mTOR pathways. However these treatments do not appear to affect the growth of a BRAF/NRAS wild type cell line (T1527A).

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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