CCRCC CELLS WITH NF2 MUTATION RESPOND TO RECOMBINANT ERK AND AKT INHIBITOR TREATMENT

The FERM domain protein, merlin, encoded by the NF2 tumor suppressor gene, regulates cell proliferation and plays a critical role in cell adhesion and motility while its loss can result in cancer development and metastasis in mice. The cellular mechanism in which merlin controls cancer cell proliferation and tumorigenesis in human clear cell renal cell carcinoma (ccRCC), however, is unknown. To address this question, we generated xenograft tumor models using a patient-derived ccRCC cell line, JHRCC12, that contained a splice site mutation in the NF2 gene. As expected, the tumors of the xenograft models developed metastatic lesions in the lungs and lymph nodes, which recapitulated the patient’s phenotype. Cells with reconstituted NF2 showed decreased cell proliferation and colony formation. More importantly, expression of NF2 significantly suppressed tumor growth in vivo. Mechanistically, NF2 controls cancer cell proliferation through negative-regulation of the PI3K-AKT and MAPK-ERK signaling pathways. When we applied inhibitors that targeted both pathways in vitro, we blocked cancer cell proliferation. Our data suggests that a combination inhibition of the PI3K and MAPK signaling pathways may serve as a therapeutic treatment for NF2-loss ccRCC.