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bioRxiv · 10.1101/750489

Targeting effector pathways in RAC1P29S-driven malignant melanoma

Uribe-Alvarez, C.·Guerrero-Rodriguez, S. L.·Rhodes, J.·Cannon, A.·Chernoff, J.·Araiza-Olivera, D.
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Abstract

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 PI3K-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.

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Uribe-Alvarez, C., Guerrero-Rodriguez, S. L., Rhodes, J., Cannon, A., Chernoff, J., Araiza-Olivera, D.. 2019-08-28. Targeting effector pathways in RAC1P29S-driven malignant melanoma. https://doi.org/10.1101/750489

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