title: A chemical biology approach identified PI3K as a potential therapeutic target for neurofibromatosis type 2.
abstract: Mutations in the merlin tumor suppressor gene cause Neurofibromatosis type 2 (NF2), which is a disease characterized by development of multiple benign tumors in the nervous system. The current standard of care for NF2 calls for surgical resection of the characteristic tumors, often with devastating neurological consequences. There are currently no approved non-surgical therapies for NF2. In an attempt to identify much needed targets and therapeutically active compounds for NF2 treatment, we employed a chemical biology approach using ultra-high-throughput screening. To support this goal, we created a merlin-null mouse Schwann cell (MSC) line to screen for compounds that selectively decrease their viability and proliferation. We optimized conditions for 384-well plate assays and executed a proof-of-concept screen of the Library of Pharmacologically Active Compounds. Further confirmatory and selectivity assays identified phosphatidylinositol 3-kinase (PI3K) as a potential NF2 drug target. Notably, loss of merlin function is associated with activation of the PI3K/Akt pathway in human schwannomas. We report that AS605240, a PI3K inhibitor, decreased merlin-null MSC viability in a dose-dependent manner without significantly decreasing viability of control Schwann cells. AS605240 exerted its action on merlin-null MSCs by promoting caspase-dependent apoptosis and inducing autophagy. Additional PI3K inhibitors tested also decreased viability of merlin-null MSCs in a dose-dependent manner. In summary, our chemical genomic screen and subsequent hit validation studies have identified PI3K as potential target for NF2 therapy.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida Florida, U.S.A.
authors.forename: Alejandra M
authors.initials: AM
authors.lastname: Petrilli
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida Florida, U.S.A.
authors.forename: Marisa A
authors.initials: MA
authors.lastname: Fuse
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida Florida, U.S.A.
authors.forename: Mathew S
authors.initials: MS
authors.lastname: Donnan
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida Florida, U.S.A.
authors.forename: Marga
authors.initials: M
authors.lastname: Bott
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida Florida, U.S.A.
authors.forename: Nicklaus A
authors.initials: NA
authors.lastname: Sparrow
authors.affiliation: Cenix BioScience GmbH Dresden, Germany ; Current affiliation: Silence Therapeutics Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tondera
authors.affiliation: Cenix BioScience GmbH Dresden, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Huffziger
authors.affiliation: Cenix BioScience GmbH Dresden, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Frenzel
authors.affiliation: Drug Discovery and Pharmacology, Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute Orlando-Lake Nona, Florida, U.S.A.
authors.forename: C Siobhan
authors.initials: CS
authors.lastname: Malany
authors.affiliation: Cenix BioScience GmbH Dresden, Germany.
authors.forename: Christophe J
authors.initials: CJ
authors.lastname: Echeverri
authors.affiliation: Drug Discovery and Pharmacology, Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute Orlando-Lake Nona, Florida, U.S.A.
authors.forename: Layton
authors.initials: L
authors.lastname: Smith
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida Florida, U.S.A.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fernández-Valle
keywords: Neurofibromatosis type 2; PI3K; PI3K inhibitor; apoptosis; autophagy; phenotypic high-throughput screen