Dual inhibition of V600EBRAF and the PI3K/AKT/mTOR pathway cooperates to induce apoptosis in melanoma cells through a MEK-independent mechanism

摘要: BRAF is a main oncogene in human melanomas. Here, we show that depletion by siRNA or inhibition of its activity treatment with RAF inhibitor Sorafenib induces apoptosis NPA melanoma cells expressing oncogenic (V600E)BRAF. This effect mediated through MEK/ERK-independent mechanism, since the MEK U0126 does not exert any effect. Moreover, demonstrate PI3K/AKT/mTOR cascade alone increase these cells. However, blockage this pathway lacking either expression cooperates to induce higher levels than those achieved alone. Consistently, abrogation increases AKT and mTOR phosphorylation, suggesting existence compensatory pro-survival mechanism after depletion. Together, our data provide rationale for dual targeting signalling effectively control disease.