title: Discovery of a small molecule targeting IRA2 deletion in budding yeast and neurofibromin loss in malignant peripheral nerve sheath tumor cells.
abstract: Malignant peripheral nerve sheath tumor (MPNST) is a life-threatening complication of neurofibromatosis type 1 (NF1). NF1 is caused by mutation in the gene encoding neurofibromin, a negative regulator of Ras signaling. There are no effective pharmacologic therapies for MPNST. To identify new therapeutic approaches targeting this dangerous malignancy, we developed assays in NF1(+/+) and NF1(-/-) MPNST cell lines and in budding yeast lacking the NF1 homologue IRA2 (ira2Δ). Here, we describe UC1, a small molecule that targets NF1(-/-) cell lines and ira2Δ budding yeast. By using yeast genetics, we identified NAB3 as a high-copy suppressor of UC1 sensitivity. NAB3 encodes an RNA binding protein that associates with the C-terminal domain of RNA Pol II and plays a role in the termination of nonpolyadenylated RNA transcripts. Strains with deletion of IRA2 are sensitive to genetic inactivation of NAB3, suggesting an interaction between Ras signaling and Nab3-dependent transcript termination. This work identifies a lead compound and a possible target pathway for NF1-associated MPNST, and shows a novel model system approach to identify and validate target pathways for cancer cells in which NF1 loss drives tumor formation.
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Dartmouth Medical School, 7650 Remsen, Hanover, NH 03755, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wood
authors.forename: Melissa
authors.initials: M
authors.lastname: Rawe
authors.forename: Gunnar
authors.initials: G
authors.lastname: Johansson
authors.forename: Shu
authors.initials: S
authors.lastname: Pang
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Soderquist
authors.forename: Ami V
authors.initials: AV
authors.lastname: Patel
authors.forename: Sandra
authors.initials: S
authors.lastname: Nelson
authors.forename: William
authors.initials: W
authors.lastname: Seibel
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Sanchez
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D055808:Drug Discovery; D004843:Epistasis, Genetic; D020690:GTPase-Activating Proteins / Q000235:genetics*; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D015972:Gene Expression Regulation, Neoplastic; D057166:High-Throughput Screening Assays; D006801:Humans; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy*; D025542:Neurofibromin 1 / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D012680:Sensitivity and Specificity; D054852:Small Molecule Libraries; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: C569422:(3-(3-bromophenyl)-1-phenylpyrazol-4-yl)methyl carbamimidothioate; D000970:Antineoplastic Agents; C118305:CTDK-I protein complex, S cerevisiae; D020690:GTPase-Activating Proteins; C064960:IRA2 protein, S cerevisiae; C090564:NAB3 protein, S cerevisiae; D025542:Neurofibromin 1; D009687:Nuclear Proteins; D011720:Pyrazoles; D016601:RNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries; D011494:Protein Kinases; D013890:Thiourea