PT  - JOURNAL ARTICLE
AU  - Cristina Uribe-Alvarez
AU  - Sandra Lucía Guerrero-Rodríguez
AU  - Jennifer Rhodes
AU  - Alexa Cannon
AU  - Jonathan Chernoff
AU  - Daniela Araiza-Olivera
TI  - Targeting effector pathways in RAC1<sup>P29S</sup>-driven malignant melanoma
AID  - 10.1101/750489
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 750489
4099  - http://biorxiv.org/content/early/2019/08/28/750489.short
4100  - http://biorxiv.org/content/early/2019/08/28/750489.full
AB  - Malignant melanoma is characterized by mutations in a number of driver genes, most notably BRAF and NRAS. Recently, genomic analyses revealed that 4-9% of sun-exposed melanoma 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/MITF in melanocytes and/or in a zebrafish model. We demonstrate that a selective Group A PAK inhibitor (Frax-1036) and certain PI3Ks inhibitors (BKM120, TGX221, GSK2636771) impede the growth of melanoma cells driven by mutant RAC1 but not mutant BRAF, however other PI3K inhibitors, including PI3Kα-selective inhibitors are less effective. Similar results were seen in vivo, using embryonic zebrafish development as a readout, but now including an SRF/MRTF inhibitor (CCG-203971). These results suggest that targeting Group A PAKs and/or SRF/MRTF represent promising approach to suppress RAC1 signaling in malignant melanoma.