Combination Small Molecule MEK and PI3K Inhibition Enhances Uveal Melanoma Cell Death in a Mutant GNAQ and GNA11 Dependent Manner
- Jahan S. Khalili1,
- Xiaoxing Yu1,
- Ji Wang2,
- Brendan C. Hayes1,
- Michael A. Davies3,
- Gregory Lizee4,
- Bita Esmaeli5, and
- Scott E. Woodman6,*
+ Author Affiliations
1Melanoma Medical Oncology, MD Anderson Cancer Center
2Thoracic and Cardiovascular surgery, MD Anderson cancer Center
3Melanoma Medical Oncology and Systems Biology, M. D. Anderson Cancer Center
4Melanoma Medical Oncology, M.D. Anderson Cancer Center
5Head and Neck Surgery, Section of Ophthalmology, MD Anderson Cancer Center
6Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center
Purpose: Activating-Q209L/P mutations in GNAQ or GNA11 (GNAQ/11) are present in ∼80% of uveal melanomas (UM). Mutant GNAQ/11 are not currently therapeutically targetable. Inhibiting key downstream effectors of GNAQ/11 represents a rational therapeutic approach for UMs that harbor these mutations. The MEK/MAPK and PI3K/AKT pathways are activated in UM. In this study, we test the effect of the clinically relevant small molecule inhibitors GSK1120212 (MEK inhibitor) and GSK2126458 (pan class I PI3K inhibitor) on UM cells with different GNAQ/11 mutations. Experimental Design: We use the largest set of genetically annotated uveal melanoma cell lines to-date to perform in vitro cellular signaling, cell cycle regulation, growth and apoptosis analyses. RNA interference and small molecule MEK and/or PI3K inhibitor treatment were employed to determine the dependency of cells with different GNAQ/11 mutation backgrounds on MEK/MAPK and/or PI3K/AKT signaling. Proteomic network analysis was performed to unveil signaling alterations in response to MEK and/or PI3K inhibition. Results: GNAQ/11 mutation status was not a determinant of whether cells would undergo cell cycle arrest or growth inhibition to MEK and/or PI3K inhibition. A reverse correlation was observed between MAPK and AKT phosphorylation after MEK or PI3K inhibition, respectively. Neither MEK nor PI3K inhibition alone was sufficient to induce apoptosis in the majority of cell lines; however, the combination of MEK + PI3K inhibitor treatment caused marked apoptosis in a GNAQ/11 mutant-dependent manner. Conclusions: MEK + PI3K inhibition may be an effective combination therapy in uveal melanoma given the inherent reciprocal activation of these pathways in UM.
- Received December 14, 2011.
- Revision received May 30, 2012.
- Accepted June 1, 2012.
- Copyright © 2012, American Association for Cancer Research.