Targeting effector pathways in RAC1P29S-driven malignant melanoma
Por:
Uribe-Alvarez C., Guerrero-Rodríguez S.L., Rhodes J., Cannon A., Chernoff J., Araiza-Olivera D.
Ahead of Print:
1 ene 2020
Resumen:
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 signalling 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 PI3Kß inhibitors (TGX221, GSK2636771) impede the growth of melanoma cells driven by mutant RAC1 but not by mutant BRAF, while other PI3K selective inhibitors, including PI3Ka, d and ?, are less effective. Using these compounds as well as an SRF/MRTF inhibitor (CCG-203,971), we observed similar results in vivo, using embryonic zebrafish development as a readout. These results suggest that targeting Group A PAKs, PI3Kß, and/or SRF/MRTF represent a promising approach to suppress RAC1 signalling in malignant melanoma. © 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group.
Filiaciones:
Uribe-Alvarez C.:
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, United States
Guerrero-Rodríguez S.L.:
Instituto de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
Rhodes J.:
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, United States
Cannon A.:
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, United States
School of Medicine, Drexel University, Philadelphia, PA, United States
Chernoff J.:
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, United States
Araiza-Olivera D.:
Instituto de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
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