PUBLICATION
Targeting effector pathways in RAC1P29S-driven malignant melanoma
- Authors
- Uribe-Alvarez, C., Guerrero-Rodríguez, S.L., Rhodes, J., Cannon, A., Chernoff, J., Araiza-Olivera, D.
- ID
- ZDB-PUB-200212-12
- Date
- 2020
- Source
- Small GTPases 12(4): 273-281 (Journal)
- Registered Authors
- Chernoff, Jonathan, Rhodes, Jennifer
- Keywords
- PAK, PI3K, RAC1, SRF/MRTF, melanoma, small GTPase
- MeSH Terms
-
- Animals
- Apoptosis
- p21-Activated Kinases/antagonists & inhibitors
- Trans-Activators/antagonists & inhibitors
- Humans
- Embryo, Nonmammalian/drug effects*
- Embryo, Nonmammalian/metabolism
- Embryo, Nonmammalian/pathology
- Melanoma/drug therapy*
- Melanoma/genetics
- Melanoma/metabolism
- Melanoma/pathology
- Tumor Cells, Cultured
- Signal Transduction
- Mutation*
- Zebrafish
- Phosphatidylinositol 3-Kinases/chemistry
- rac1 GTP-Binding Protein/genetics*
- Gene Expression Regulation, Neoplastic/drug effects*
- Cell Proliferation
- Serum Response Factor/antagonists & inhibitors
- Enzyme Inhibitors/pharmacology*
- PubMed
- 32043900 Full text @ Small GTPases
Citation
Uribe-Alvarez, C., Guerrero-Rodríguez, S.L., Rhodes, J., Cannon, A., Chernoff, J., Araiza-Olivera, D. (2020) Targeting effector pathways in RAC1P29S-driven malignant melanoma. Small GTPases. 12(4):273-281.
Abstract
Malignant melanoma is characterized by mutations in a number of driver genes, most notably BRAF and NRAS. Recent genomic analyses revealed that 4-9% of sun-exposed melanomas bear activating mutations in RAC1, which encodes a small GTPase that is known to play key roles in cell proliferation, survival, and migration. The RAC1 protein activates several effector pathways, including Group A p21-activated kinases (PAKs), phosphoinositol-3-kinases (PI3Ks), in particular the beta isoform, and the serum-response factor/myocardin-related transcription factor (SRF/MRTF). Having previously shown that inhibition of Group A PAKs impedes oncogenic signaling from RAC1P29S, we here extend this analysis to examine the roles of PI3Ks and SRF/MRTF in melanocytes and/or in a zebrafish model. We demonstrate that a selective Group A PAK inhibitor (Frax-1036), a pan-PI3K (BKM120), and two PI3Kβ inhibitors (TGX221, GSK2636771) impede the growth of melanoma cells driven by mutant RAC1 but not by mutant BRAF, while other PI3K selective inhibitors, including PI3Kα, δ and γ, are less effective. Using these compounds as well as an SRF/MRTF inhibitor (CCG-203971), we observed similar results in vivo, using embryonic zebrafish development as a readout. These results suggest that targeting Group A PAKs, PI3Kβ, and/or SRF/MRTF represent a promising approach to suppress RAC1 signaling in malignant melanoma.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping