Group I p21-Activated Kinases (PAKs) Promote Tumor Cell Proliferation and Survival through the AKT1 and Raf–MAPK Pathways

Group I p21-activated kinases (PAKs) are important effectors of the small GTPases Rac and Cdc42, which regulate cell motility/migration, survival, proliferation and gene transcription. Hyperactivation of these kinases have been reported in many tumor types, making PAKs attractive targets for therapeutic intervention. PAKs are activated by growth factor-mediated signaling and are negatively regulated by the tumor suppressor NF2/Merlin. Thus, tumors characterized by NF2 inactivation would be expected to show hyperactivated PAK signaling. Based on this rationale, we evaluated the status of PAK signaling in malignant mesothelioma (MM), an aggressive neoplasm that is resistant to current therapies and shows frequent inactivation of NF2. We demonstrate that group I PAKs are activated in most MMs and MM cell lines and that genetic or pharmacological inhibition of PAKs is sufficient to inhibit MM cell proliferation and survival. We also identify downstream effectors and signaling pathways that may contribute mechanistically to PAK-related tumorigenesis. Specifically, we show that inhibition of PAK results in attenuation of AKT and Raf-MAPK signaling and decreased tumor cell viability. Collectively, these data suggest that pharmacological inhibition of group I PAKs may have therapeutic efficacy in tumors characterized by PAK activation.