RAC1mutation is not a predictive biomarker for PI3'-kinase-ß-selective pathway-targeted therapy.

ABSTRACT

Mutational activation of RAC1 is detected in ~7% of cutaneous melanoma, with the most frequent mutation (RAC1C85T ) encoding for RAC1P29S . RAC1P29S is a fast-cycling GTPase that leads to accumulation of RAC1P29S -GTP, which has potentially pleiotropic regulatory functions in melanoma cell signaling and biology. However, the precise mechanism by which mutationally activated RAC1P29S propagates its pro-tumorigenic effects remains unclear. RAC1-GTP is reported to activate the beta isoform of PI3'-kinase (PIK3CB/PI3Kß) leading to downstream activation of PI3'-lipid signaling. Hence, we employed both genetic and isoform-selective pharmacological inhibitors to test if RAC1P29S propagates its oncogenic signaling in melanoma through PI3Kß. We observed that RAC1P29S -expressing melanoma cells were largely insensitive to inhibitors of PI3Kß. Furthermore, RAC1P29S melanoma cell lines showed variable sensitivity to pan-class 1 (α/ß/γ/δ) PI3'-kinase inhibitors, suggesting that RAC1-mutated melanoma cells may not rely on PI3'-lipid signaling for their proliferation. Lastly, we observed that RAC1P29S -expressing cell lines also showed variable sensitivity to pharmacological inhibition of the RAC1 â†’ PAK1 signaling pathway, questioning the relevance of inhibitors of this pathway for the treatment of patients with RAC1-mutated melanoma.