Human Endogenous Retrovirus Type K Promotes Proliferation and Confers Sensitivity to Antiretroviral Drugs in Merlin-Negative Schwannoma and Meningioma

Abstract

Deficiency of the tumor suppressor Merlin causes development of schwannoma, meningioma, and ependymoma tumors, which can occur spontaneously or in the hereditary disease neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Surgery and radiotherapy are current first-line treatments; however, tumors frequently recur with limited treatment options. Here, we use human Merlin-negative schwannoma and meningioma primary cells to investigate the involvement of the endogenous retrovirus HERV-K in tumor development. HERV-K proteins previously implicated in tumorigenesis were overexpressed in schwannoma and all meningioma grades, and disease-associated CRL4DCAF1 and YAP/TEAD pathways were implicated in this overexpression. In normal Schwann cells, ectopic overexpression of HERV-K Env increased proliferation and upregulated expression of c-Jun and pERK1/2, which are key components of known tumorigenic pathways in schwannoma, JNK/c-Jun, and RAS/RAF/MEK/ERK. Furthermore, FDA-approved retroviral protease inhibitors ritonavir, atazanavir, and lopinavir reduced proliferation of schwannoma and grade I meningioma cells. These results identify HERV-K as a critical regulator of progression in Merlin-deficient tumors and offer potential strategies for therapeutic intervention. Significance: The endogenous retrovirus HERV-K activates oncogenic signaling pathways and promotes proliferation of Merlin-deficient schwannomas and meningiomas, which can be targeted with antiretroviral drugs and TEAD inhibitors.

Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma

“…Abacavir has also been suggested to reduce proliferation and induce differentiation in malignant medulloblastoma ( 65 , 66 ). Similarly, Maze et al demonstrated that HIV protease inhibitors reduced proliferation of HERV-K + schwannomas, and meningiomas by eliminating ERK1/2 tumorigenic pathways ( 67 ). Given their favorable pharmacokinetic profile and their specificity for HERV-K, antiretroviral therapeutics may be ideal candidates for cancer drug repositioning.…”

Development of human endogenous retrovirus type K‐ related treatments for human diseases

“…Reduce proliferation of schwannoma and meningioma cells, through inhibition of HERV-K PR [31] The integrase inhibitor DTG Inhibit the proliferation of cancer cells, through repression of HERV-K expression [32] The integrase inhibitor Raltegravir Block HERV-K infection and production [26] The inhibitor of MEK, PD98059 or CDK4, 219476…”

HERVs and Cancer—A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers

“…These microvesicles were reported to carry the ability of horizontal gene transfer between cancer cells, potentially leading to increased levels of HERV proteins in neighboring cells [ 266 ]. HERV-K (HML-2) Env expression has been reported to be upregulated in human Merlin-negative schwannoma and in all meningioma grades via the CRL4 (DCAF1) and YAP/TEAD pathway [ 267 ]. In addition, C-MYC was shown to bind to the HERV-K (HML-2) LTR and lead to env expression, which in turn can be inhibited by SMARCB1 binding free C-MYC [ 268 ].…”

“…Biallelic SMARCB1 is characteristic of atypical Teratoid Rhabdoid Tumor (AT/RT), a rare pediatric central nervous system cancer [ 268 ]. HERV-K (HML-2) Env in turn increases JUN and pERK4/2 when overexpressed in Schwann cells [ 267 ], while retroviral protease inhibitors ritonavir, atazanavir, and lopinavir reduced proliferation of schwannoma and grade I meningioma cells [ 267 ]. Furthermore, ERVW-1 ε and ERVFRD-1 ε were demonstrated to bind to mitochondria of chemo-resistant U87RETO glioblastoma cells.…”