Genotype-dependent sensitivity of uveal melanoma cell lines to inhibition of B-Raf, MEK, and Akt kinases: rationale for personalized therapy.

Abstract

PURPOSE:

Inhibitors of B-Raf and MEK kinases hold promise for the management of cutaneous melanomas harboring BRAF mutations. BRAF mutations are rare in uveal melanomas (UMs), but somatic mutations in the G protein α subunits Gαq and Gα11 (encoded by GNAQ and GNA11, respectively) occur in a mutually exclusive pattern in ∼80% of UMs. The impact of B-Raf and MEK inhibitors on Gα-mutant UMs remains unknown.

METHODS:

The impact of the B-Raf inhibitor PLX4720, the MEK inhibitor AZD6244, and the Akt inhibitor MK2206 on UM cell lines was assessed with the use of cell viability, proliferation, and apoptosis assays and immunoblot analysis.

RESULTS:

BRAF-mutant UM cells were sensitive to both PLX4720 and AZD6244, undergoing cell cycle arrest but not apoptosis. UM cells with a Gα-protein mutation (GNAQ or GNA11) were mildly sensitive to AZD6244 but completely resistant to PLX4720. In fact, PLX4720 paradoxically increased ERK phosphorylation in Gα-mutant UM cells. The combination of AZD6244 with PLX4720 had synergistic anticancer activity in BRAF-mutant cells but not in Gα-mutant cells. The Akt inhibitor MK2206 sensitized BRAF-mutant cells to both PLX4720 and AZD6244 and sensitized Gα-mutant cells to AZD6244 but did not overcome the resistance of the Gα-mutant cells to PLX4720.

CONCLUSIONS:

The response of UM cells to inhibition of B-Raf, MEK, and Akt depends on their genotype. Future use of such targeted therapies in clinical trials of UM patients will require careful design and patient selection based on genotype to provide personalized and effective therapy.

• Authors: Nicholas Mitsiades, Sue Anne Chew, Bin He, Aline I Riechardt, Theano Karadedou, Vassiliki Kotoula, Vassiliki Poulaki
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 52 Issue 10 Pg. 7248-55 (Sep 14 2011) ISSN: 1552-5783 [Electronic] United States
• PMID: 21828154 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AZD 6244
• Benzimidazoles
• Heterocyclic Compounds, 3-Ring
• Indoles
• MK 2206
• PLX 4720
• Sulfonamides
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase Kinases

Topics

• Apoptosis (drug effects)
• Benzimidazoles (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Genotype
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Immunoblotting
• In Situ Nick-End Labeling
• Indoles (pharmacology)
• MAP Kinase Kinase Kinases (antagonists & inhibitors, metabolism)
• Melanoma (genetics, pathology)
• Precision Medicine
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Sulfonamides (pharmacology)
• Uveal Neoplasms (genetics, pathology)