Suppression of RAC1-driven malignant melanoma by group A PAK inhibitors

• Published in: Oncogene 2018-02, Vol.37 (7), p.944-952
• Main Authors: Araiza-Olivera, D, Feng, Y, Semenova, G, Prudnikova, T Y, Rhodes, J, Chernoff, J
• Format: Article
• Language: English
• Subjects: 13/1; 13/95; 14/63; 631/67/1813/1634; 631/80/641/83; 64/116; 82/80; Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Biology; Cell Proliferation; Cellular signal transduction; Danio rerio; Development and progression; Developmental stages; Embryo, Nonmammalian - cytology; Embryo, Nonmammalian - drug effects; Embryo, Nonmammalian - metabolism; Embryogenesis; Embryonic development; Female; Gene expression; Genetic aspects; Human Genetics; Humans; Immunosurveillance; Internal Medicine; Male; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 1 - metabolism; Medicine; Medicine & Public Health; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Mice; Mice, Nude; Mutation; Oncology; original-article; p21-activated kinase; p21-Activated Kinases - antagonists & inhibitors; p21-Activated Kinases - genetics; p21-Activated Kinases - metabolism; PD-L1 protein; Phenotypes; rac1 GTP-Binding Protein - antagonists & inhibitors; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Skin cancer; Small Molecule Libraries - pharmacology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Zebrafish; Zebrafish - growth & development; Zebrafish - metabolism
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.400

Activating mutations in the RAC1 gene have recently been discovered as driver events in malignant melanoma. Expression of this gene is associated with melanocyte proliferation, and melanoma cells bearing this mutation are insensitive to BRAF inhibitors such as vemurafenib and dabrafenib, and also may evade immune surveillance due to enhanced expression of PD-L1. Activating mutations in RAC1 are of special interest, as small-molecule inhibitors for the RAC effector p21-activated kinase (PAK) are in late-stage clinical development and might impede oncogenic signaling from mutant RAC1. In this work, we explore the effects of PAK inhibition on RAC1 P29S signaling in zebrafish embryonic development, in the proliferation, survival and motility of RAC1 P29S -mutant human melanoma cells, and on tumor formation and progression from such cells in mice. We report that RAC1 P29S evokes a Rasopathy-like phenotype on zebrafish development that can be blocked by inhibitors of PAK or MEK. We also found and that RAC1 -mutant human melanoma cells are resistant to clinical inhibitors of BRAF but are uniquely sensitive to PAK inhibitors. These data suggest that suppressing the PAK pathway might be of therapeutic benefit in this type of melanoma.