title: A high-throughput kinome screen reveals serum/glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas.
abstract: Meningiomas are the most common primary intracranial adult tumor. All Neurofibromatosis 2 (NF2)-associated meningiomas and ~60% of sporadic meningiomas show loss of NF2 tumor suppressor protein. There are no effective medical therapies for progressive and recurrent meningiomas. Our previous work demonstrated aberrant activation of mTORC1 signaling that led to ongoing clinical trials with rapamycin analogs for NF2 and sporadic meningioma patients. Here we performed a high-throughput kinome screen to identify kinases responsible for mTORC1 pathway activation in NF2-deficient meningioma cells. Among the emerging top candidates were the mTORC2-specific target serum/glucocorticoid-regulated kinase 1 (SGK1) and p21-activated kinase 1 (PAK1). In NF2-deficient meningioma cells, inhibition of SGK1 rescues mTORC1 activation, and SGK1 activation is sensitive to dual mTORC1/2 inhibitor AZD2014, but not to rapamycin. PAK1 inhibition also leads to attenuated mTORC1 but not mTORC2 signaling, suggesting that mTORC2/SGK1 and Rac1/PAK1 pathways are independently responsible for mTORC1 activation in NF2-deficient meningiomas. Using CRISPR-Cas9 genome editing, we generated isogenic human arachnoidal cell lines (ACs), the origin cell type for meningiomas, expressing or lacking NF2. NF2-null CRISPR ACs recapitulate the signaling of NF2-deficient meningioma cells. Interestingly, we observe increased SGK1 transcription and protein expression in NF2-CRISPR ACs and in primary NF2-negative meningioma lines. Moreover, we demonstrate that the dual mTORC1/mTORC2 inhibitor, AZD2014 is superior to rapamycin and PAK inhibitor FRAX597 in blocking proliferation of meningioma cells. Importantly, AZD2014 is currently in use in several clinical trials of cancer. Therefore, we believe that AZD2014 may provide therapeutic advantage over rapalogs for recurrent and progressive meningiomas.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Roberta L
authors.initials: RL
authors.lastname: Beauchamp
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Marianne F
authors.initials: MF
authors.lastname: James
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: DeSouza
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Vilas
authors.initials: V
authors.lastname: Wagh
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Wen-Ning
authors.initials: WN
authors.lastname: Zhao
authors.affiliation: Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Jordan
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Anat
authors.initials: A
authors.lastname: Stemmer-Rachamimov
authors.affiliation: Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Plotkin
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Chemical Neurobiology Laboratory, Departments of Neurology and Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Ramesh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D015151:Immunoblotting; D008577:Meningeal Neoplasms / Q000201:enzymology* / Q000235:genetics; D008579:Meningioma / Q000201:enzymology* / Q000235:genetics; D009025:Morpholines / Q000494:pharmacology; D016518:Neurofibromatosis 2 / Q000235:genetics; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011743:Pyrimidines; D015398:Signal Transduction / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D017874:Immediate-Early Proteins; D009025:Morpholines; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D000099184:Serum-Glucocorticoid Regulated Kinases; C585537:vistusertib
keywords: AZD2014; NF2; SGK1; mTOR signaling; meningioma