Inhibition of the RAC/PAK Signaling Axis Enhances the Potency of MAPK Cascade Inhibitors Against Uveal Melanoma
Abstract
1. Introduction
2. Materials and Methods
2.1. Cell Culture and Reagents
2.2. Western Blotting and Antibodies
2.3. Rac1 Activity Assay
2.4. Cell Number Comparison in Treated Cultures
2.5. EdU-Incorporation Assay
2.6. Quantitative Reverse Transcription PCR (qRT-PCR)
2.7. Animal Experimentation
2.8. Comparison of Intracellular GTP Content
2.9. Statistical Methods
3. Results
3.1. GNAQ- and GNA11-Mutant Uveal Melanomas Are Vulnerable to PAK Inhibition
3.2. Inhibitors of the RAC/PAK Signaling Axis Synergize with the MEK Inhibitors in Uveal Melanoma Cells
3.3. Inhibitors of GTP Biosynthesis Synergize with MEK Inhibitors in Uveal Melanoma Cells
3.4. Enhanced Suppression of the MAPK Signaling Cascade by Combined Treatments
3.5. An IMPDHi and MEKi Combination Reduces the Expression of EGR1 in Uveal Melanoma Cells
3.6. An IMPDH Inhibitor Enhances the Potency of a MEK Inhibitor Against Uveal Melanoma In Vivo
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
BIN | Binimetinib. |
COB | Cobimetinib. |
EHT | EHT1864. |
GPCR | G-protein coupled receptor. |
IMPDHi | Inhibitor of inosine monophosphate dehydrogenase (IMPDH). |
MAPK | Mitogen-activated protein kinase |
MEKi | Inhibitor of mitogen-activated protein kinase kinase (MEK). |
MIR | Mirdametinib |
MIZ | Mizoribine. |
PAKi | Inhibitor of p21-activated protein kinase (PAK). |
PF | PF-3758309. |
RACi | Inhibitor of Ras-related C3 botulinum toxin substrate (RAC). |
RBV | Ribavirin. |
SEL | Selumetinib. |
UM | Uveal melanoma |
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Maslov, A.A.; Trageser, N.H.; Kichina, J.V.; Elamir, H.; Gardner, E.; Teaman, F.; Vishwanath, V.; Dugas, S.M.; Heid, J.; Maslov, A.Y.; et al. Inhibition of the RAC/PAK Signaling Axis Enhances the Potency of MAPK Cascade Inhibitors Against Uveal Melanoma. Biomolecules 2025, 15, 1425. https://doi.org/10.3390/biom15101425
Maslov AA, Trageser NH, Kichina JV, Elamir H, Gardner E, Teaman F, Vishwanath V, Dugas SM, Heid J, Maslov AY, et al. Inhibition of the RAC/PAK Signaling Axis Enhances the Potency of MAPK Cascade Inhibitors Against Uveal Melanoma. Biomolecules. 2025; 15(10):1425. https://doi.org/10.3390/biom15101425
Chicago/Turabian StyleMaslov, Alexei A., Nicholas H. Trageser, Julia V. Kichina, Haya Elamir, Evelyn Gardner, Frances Teaman, Vera Vishwanath, Scott M. Dugas, Johanna Heid, Alexander Y. Maslov, and et al. 2025. "Inhibition of the RAC/PAK Signaling Axis Enhances the Potency of MAPK Cascade Inhibitors Against Uveal Melanoma" Biomolecules 15, no. 10: 1425. https://doi.org/10.3390/biom15101425
APA StyleMaslov, A. A., Trageser, N. H., Kichina, J. V., Elamir, H., Gardner, E., Teaman, F., Vishwanath, V., Dugas, S. M., Heid, J., Maslov, A. Y., Withers, H. G., Bianchi-Smiraglia, A., Leonova, K. I., Nikiforov, M. A., & Kandel, E. S. (2025). Inhibition of the RAC/PAK Signaling Axis Enhances the Potency of MAPK Cascade Inhibitors Against Uveal Melanoma. Biomolecules, 15(10), 1425. https://doi.org/10.3390/biom15101425