Heterogeneity in Mitogen-Activated Protein Kinase (MAPK) Pathway Activation in Uveal Melanoma With Somatic GNAQ and
Getachew Boru1, Colleen M Cebulla1, Klarke M Sample1
1Department of Ophthalmology, the Ohio State University, Columbus, Ohio, Unites States.
Purpose:
The activation of the mitogen-activated protein kinase (MAPK) pathway has been suggested as the major downstream target when GNAQ and GNA11 (GNAQ/11) are mutated in uveal melanoma (UM). However, clinical trials with single agent MEK inhibitor showed no clinical significance in altering the overall outcome of the disease in UM; therefore, we investigated the correlation between naturally occurring mutations in GNAQ/11 and activation of MAPK pathway in vivo in primary UM.
Methods:
Screening for activating mutations in codons 183 and 209 of GNAQ/11 was carried out by sequencing and restriction fragment length polymorphism (RFLP) in a cohort of 42 primary UM. Activation of the MAPK pathway and other potential downstream signals was assessed by immunohistochemistry and/or Western blot analysis. Potential downstream signaling of mutant and wild type GNAQ/11 was studied by transient transfection assay in nonmutant cell lines.
Results:
Somatic mutations in GNAQ/11 were observed in 35/42 (83.3%) of primary UM. Tumors with GNAQ/11 mutations showed variations in the activation of ERK1/2 with significant tumor heterogeneity. Weak and undetectable ERK1/2 activation was observed in 4/35 (11.4%) and 8/35 (22.9%) of the GNAQ/11 mutant UM, respectively. Tumor heterogeneity of GNAQ/11 mutations was also observed in a subset of tumors.
Conclusions:
Our results indicate that there is marked variation in MAPK activation in UM with GNAQ/11 mutations. Thus, GNAQ/11 mutational status is not a sufficient biomarker to adequately predict UM patient responses to single-agent selective MEK inhibitor therapy.
Insights
GNAQ/11 mutations in uveal melanoma (UM) do not consistently activate the MAPK pathway. This tumor heterogeneity means GNAQ/11 status alone cannot predict patient response to MEK inhibitor therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The mitogen-activated protein kinase (MAPK) pathway is a proposed downstream target of GNAQ and GNA11 (GNAQ/11) mutations in uveal melanoma (UM).
- Previous clinical trials using single-agent MEK inhibitors have shown limited efficacy in UM, prompting further investigation into the underlying molecular mechanisms.
Purpose of the Study:
- To investigate the correlation between GNAQ/11 mutations and MAPK pathway activation in primary UM.
- To assess the clinical utility of GNAQ/11 mutational status as a predictive biomarker for MEK inhibitor therapy.
Main Methods:
- Sequencing and RFLP were used to screen 42 primary UM samples for GNAQ/11 mutations.
- Immunohistochemistry and Western blot analysis assessed MAPK pathway activation (ERK1/2).
- Transient transfection assays studied downstream signaling of mutant and wild-type GNAQ/11.
Main Results:
- Somatic GNAQ/11 mutations were identified in 83.3% of primary UM.
- Significant tumor heterogeneity in ERK1/2 activation was observed among GNAQ/11 mutant UM.
- Weak or undetectable ERK1/2 activation was noted in 11.4% and 22.9% of mutant UM, respectively.
Conclusions:
- MAPK pathway activation in UM with GNAQ/11 mutations exhibits considerable variation.
- GNAQ/11 mutational status alone is insufficient to predict patient response to selective MEK inhibitor therapy in UM.
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