p21-activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model

摘要: The RAS genes are the most commonly mutated oncogenes in human cancer and present a particular therapeutic dilemma, as direct targeting of Ras proteins by small molecules has proved difficult. Signaling pathways downstream Ras, Raf/Mek/Erk PI3K/Akt/mTOR, dominated lipid protein kinases that provide attractive alternate targets Ras-driven tumors. As p21-activated kinase 1 (Pak1) been shown to regulate both these signaling is itself upregulated many cancers, we assessed role Pak1 skin cancer. In squamous cell carcinoma (SCC), found strong positive correlation between advanced stage grade PAK1 expression. Using mouse model Kras-driven SCC, showed deletion gene led markedly decreased tumorigenesis progression, accompanied near total loss Erk Akt activity. Treatment KrasG12D mice with either two distinct molecule Pak inhibitors (PF03758309 FRAX597) caused tumor regression Tumor was also seen treated specific Mek inhibitor, but not an inhibitor. These findings establish new target KRAS-driven tumors suggest mechanism action through Erk, Akt, pathway.