Kinome Screen Reveals SGK1 as a Therapeutic Target for NF2: Inhibition of mTORC1/2 is More Effective than Rapamycin

Abstract

Neurofibromatosis type 2 (NF2) is characterized by vestibular schwannomas and meningiomas (MN) due to bi-allelic NF2 inactivation with loss of NF2 tumor suppressor protein. Besides NF2-associated MNs, ~60% of sporadic MNs show loss of NF2, and these tumors are non-responsive to chemotherapeutic intervention. We previously showed activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling upon NF2 loss, leading to clinical trials with rapalogs. Here we carried out a high throughput kinome screen to identify kinases responsible for mTORC1 activation in NF2-null MN cells. Among the top candidates were the mTORC2-specific target serum/glucocorticoid-regulated kinase 1 (SGK1) and p21-activated kinase 1 (PAK1). In NF2-null MNs, SGK1 inhibition rescues mTORC1 activation, and SGK1 activation is sensitive to dual mTORC1/2 inhibitor AZD2014, but not to rapamycin. PAK1 inhibition also rescues mTORC1 activation, but in a manner independent of mTORC2/SGK1 signaling. Using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas genome editing we generated isogenic arachnoidal cell lines (ACs), the origin cell type for MNs, with or without NF2. NF2-null CRISPR ACs recapitulates the signaling of NF2-null MN cells. Interestingly, we observe increased SGK1 transcription and protein expression in NF2-CRISPR ACs and in primary NF2 MN lines.Moreover, AZD2014 treatment of NF2-null MN cells leads to decreased cell viability and shows greater efficacy than rapamycin. Therefore, inhibiting mTORC1 and mTORC2 signaling is a critical step for potential therapeutic interventions for NF2.