PP03. HUMAN ENDOGENOUS RETROVIRUS TYPE K (HERVK) PROTEINS ARE OVEREXPRESSED AND RELEASED FROM HUMAN PRIMARY SCHWANNOMA CELLS CONTRIBUTING TO TUMOUR DEVELOPMENT VIA ERK AKT FAK PATHWAYS ACTIVATION AND P53 DOWNREGULATION

摘要

Loss of function mutations in the gene coding for the tumour suppressor Merlin causes development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas. These tumours may occur spontaneously or as a part of the hereditary disease Neurofibromatosis type 2 (NF2). Current therapies, surgery and radiosurgery, are not fully effective and new drug treatments are urgently needed. Schwannoma is the most common Merlin-deficient tumour, a hallmark for NF2 and a model for all other Merlin-deficient tumours. Therefore, to study Merlin-deficient tumours and to test different drugs we have developed a schwannoma in vitro cell model. Using this model we have previously identified several targets and tested various drugs including Sorafenib, which we have in phase 0 clinical trials on NF2 patients. Our preliminary data suggest that a promising target for Merlin-deficient tumours is one group of endogenous retroviruses called HERVK (Human Endogenous Retrovirus type K). Endogenous retroviruses are viruses that have integrated themselves into germ-line chromosomes and thereby become part of human genome (8%). HERVK are overexpressed in several cancers and activate pathways known to be involved in schwannoma development such as NFkB, β-catenin, ERK and AKT. HERVK proteins are currently being investigated as potential immunotherapy targets for cancer and HIV. We find that HERVK envelope, capsid/gag, Rec and Np9 proteins are overexpressed in human primary schwannoma cells and tissues. Additionally, HERVK envelope and capsid proteins are released from schwannoma cells. HERVK envelope expression is Merlin dependent and both HERVK envelope and capcid/gag expression are transcriptionally and translationally regulated. Anti-HERVK antibodies reduced schwannoma proliferation, pERK/pAKT/ pFAK and cyclin D1 levels and increased expression of p53. Also, pre-incubation of schwannoma cells with anti-HERVK antibodies prior to treatment with Selumetinib potentiated drug’s efficiency. An HIV protease inhibitor with some potency for HERVK protease, Ritonavir, also decreased proliferation of schwannoma cells and increased the efficiency of Selumetinib, Sorafenib and BEZ235 when combined. We suggest that HERVK plays a relevant role in schwannoma and other Merlin-deficient tumours development.