title: NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition.
abstract: Ch22q LOH is preferentially associated with RAS mutations in papillary and in poorly differentiated thyroid cancer (PDTC). The 22q tumor suppressor NF2, encoding merlin, is implicated in this interaction because of its frequent loss of function in human thyroid cancer cell lines. Nf2 deletion or Hras mutation is insufficient for transformation, whereas their combined disruption leads to murine PDTC with increased MAPK signaling. Merlin loss induces RAS signaling in part through inactivation of Hippo, which activates a YAP-TEAD transcriptional program. We find that the three RAS genes are themselves YAP-TEAD1 transcriptional targets, providing a novel mechanism of promotion of RAS-induced tumorigenesis. Moreover, pharmacologic disruption of YAP-TEAD with verteporfin blocks RAS transcription and signaling and inhibits cell growth. The increased MAPK output generated by NF2 loss in RAS-mutant cancers may inform therapeutic strategies, as it generates greater dependency on the MAPK pathway for viability.
  
  
  CONCLUSIONS
  Intensification of mutant RAS signaling through copy-number imbalances is commonly associated with transformation. We show that NF2/merlin inactivation augments mutant RAS signaling by promoting YAP/TEAD-driven transcription of oncogenic and wild-type RAS, resulting in greater MAPK output and increased sensitivity to MEK inhibitors.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Maria E R
authors.initials: ME
authors.lastname: Garcia-Rendueles
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Ricarte-Filho
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Untch
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Iňigo
authors.initials: I
authors.lastname: Landa
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Knauf
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Francesca
authors.initials: F
authors.lastname: Voza
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Vicki E
authors.initials: VE
authors.lastname: Smith
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ian
authors.initials: I
authors.lastname: Ganly
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yogindra
authors.initials: Y
authors.lastname: Persaud
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Gisele
authors.initials: G
authors.lastname: Oler
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Jhanwar
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kety H
authors.initials: KH
authors.lastname: Huberman
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Filippo
authors.initials: F
authors.lastname: Giancotti
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ronald
authors.initials: R
authors.lastname: Ghossein
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York. faginj@mskcc.org.
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
mesh_terms: D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023061:Gene Order; D018390:Gene Targeting; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D009367:Neoplasm Staging; D025581:Neurofibromin 2 / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism*; D059372:Nucleotide Motifs; D056510:Position-Specific Scoring Matrices; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D018797:Cell Cycle Proteins; D025581:Neurofibromin 2; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D020928:Mitogen-Activated Protein Kinases