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
  • Cell Proliferation
  • Embryo, Nonmammalian/drug effects*
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/pathology
  • Enzyme Inhibitors/pharmacology*
  • Gene Expression Regulation, Neoplastic/drug effects*
  • Humans
  • Melanoma/drug therapy*
  • Melanoma/genetics
  • Melanoma/metabolism
  • Melanoma/pathology
  • Mutation*
  • Phosphatidylinositol 3-Kinases/chemistry
  • Serum Response Factor/antagonists & inhibitors
  • Signal Transduction
  • Trans-Activators/antagonists & inhibitors
  • Tumor Cells, Cultured
  • Zebrafish
  • p21-Activated Kinases/antagonists & inhibitors
  • rac1 GTP-Binding Protein/genetics*
PubMed
32043900 Full text @ Small GTPases
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
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping