biostudies-literatureMaslov AARoswell Park Alliance FoundationNCI NIH HHSNIH HHS1425https://www.ebi.ac.uk/biostudies/studies/S-EPMC12564536biostudies-literatureUnknown15(10)Uveal melanoma is a melanocyte-derived malignancy of the eye with a high propensity for liver metastasis. Metastatic uveal melanoma is associated with high mortality and is poorly responsive to currently available therapies. Most uveal melanoma cases are driven by activating mutations in GNAQ and GNA11 genes, which convey oncogenic signaling through the mitogen-activated protein kinase (MAPK) pathway. Despite promising early results, safe doses of pharmacological inhibitors of the MAPK cascade failed to effectively control uveal melanoma in human trials. Considering the role of the RAC/PAK signaling axis as a co-regulator of the MAPK cascade, we set forth to investigate whether the efficacy of MAPK cascade inhibitors in pre-clinical models may be enhanced by direct inhibition of RAC and PABiomoleculesInhibition of the RAC/PAK Signaling Axis Enhances the Potency of MAPK Cascade Inhibitors Against Uveal Melanoma.PMC12564536R37 CA2480181R37CA248018-05NAP30 CA016056R01 CA2244341P30CA016056-471R01CA224434-05Gardner EBianchi-Smiraglia ADugas SMTrageser NHKichina JVNikiforov MAKandel ESElamir HLeonova KIWithers HGMaslov AYTeaman FMaslov AAVishwanath VHeid JfalseInhibition of the RAC/PAK Signaling Axis Enhances the Potency of MAPK Cascade Inhibitors Against Uveal Melanoma.Uveal melanoma is a melanocyte-derived malignancy of the eye with a high propensity for liver metastasis. Metastatic uveal melanoma is associated with high mortality and is poorly responsive to currently available therapies. Most uveal melanoma cases are driven by activating mutations in GNAQ and GNA11 genes, which convey oncogenic signaling through the mitogen-activated protein kinase (MAPK) pathway. Despite promising early results, safe doses of pharmacological inhibitors of the MAPK cascade failed to effectively control uveal melanoma in human trials. Considering the role of the RAC/PAK signaling axis as a co-regulator of the MAPK cascade, we set forth to investigate whether the efficacy of MAPK cascade inhibitors in pre-clinical models may be enhanced by direct inhibition of RAC and PA2025-01-01T00:00:00Z2025 Oct2026-05-14T03:18:54.518Z2026-05-14T03:12:14.893ZS-EPMC125645364115465410.3390/biom15101425