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

Mutational activation of RAC1 is detected in ~7% of cutaneous melanoma, with the most frequent mutation (RAC1^C85T ) encoding for RAC1^P29S . RAC1^P29S is a fast-cycling GTPase that leads to accumulation of RAC1^P29S -GTP, which has potentially pleiotropic regulatory functions in melanoma cell signaling and biology. However, the precise mechanism by which mutationally activated RAC1^P29S propagates its pro-tumorigenic effects remains unclear. RAC1-GTP is reported to activate the beta isoform of PI3'-kinase (PIK3CB/PI3Kβ) leading to downstream activation of PI3'-lipid signaling. Hence, we employed both genetic and isoform-selective pharmacological inhibitors to test if RAC1^P29S propagates its oncogenic signaling in melanoma through PI3Kβ. We observed that RAC1^P29S -expressing melanoma cells were largely insensitive to inhibitors of PI3Kβ. Furthermore, RAC1^P29S melanoma cell lines showed variable sensitivity to pan-class 1 (α/β/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 RAC1^P29S -expressing cell lines also showed variable sensitivity to pharmacological inhibition of the RAC1 → PAK1 signaling pathway, questioning the relevance of inhibitors of this pathway for the treatment of patients with RAC1-mutated melanoma.