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Suppression of RAC1-driven malignant melanoma by group A PAK inhibitors


Activating mutations in the RAC1 gene have recently been discovered as driver events in malignant melanoma. Expression of this gene is associated with melanocyte proliferation, and melanoma cells bearing this mutation are insensitive to BRAF inhibitors such as vemurafenib and dabrafenib, and also may evade immune surveillance due to enhanced expression of PD-L1. Activating mutations in RAC1 are of special interest, as small-molecule inhibitors for the RAC effector p21-activated kinase (PAK) are in late-stage clinical development and might impede oncogenic signaling from mutant RAC1. In this work, we explore the effects of PAK inhibition on RAC1P29S signaling in zebrafish embryonic development, in the proliferation, survival and motility of RAC1P29S-mutant human melanoma cells, and on tumor formation and progression from such cells in mice. We report that RAC1P29S evokes a Rasopathy-like phenotype on zebrafish development that can be blocked by inhibitors of PAK or MEK. We also found and that RAC1-mutant human melanoma cells are resistant to clinical inhibitors of BRAF but are uniquely sensitive to PAK inhibitors. These data suggest that suppressing the PAK pathway might be of therapeutic benefit in this type of melanoma.

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We thank Drs Ruth Halaban and Meenhard Herlyn for providing melanoma cell lines, and Dr Rebecca Burdine for Tg(cmlc2:EGFP) zebrafish, Genentech for providing Frax-1036 and the Fox Chase Cancer Center Animal Facility for assistance with zebrafish experiments. This work was supported by R01CA227184 (JC), NIH CORE Grant P30 CA006927, and an appropriation from the state of Pennsylvania to the Fox Chase Cancer Center.

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Correspondence to J Chernoff.

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Araiza-Olivera, D., Feng, Y., Semenova, G. et al. Suppression of RAC1-driven malignant melanoma by group A PAK inhibitors. Oncogene 37, 944–952 (2018).

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