NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition
Copyright policy )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. Significance: 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. Cancer Discov; 5(11); 1178–93. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 1111
- University of California, San Francisco United States
- Memorial Sloan Kettering Cancer Center United States
Chromosomes, Human, Pair 22, Drug Resistance, Cell Cycle Proteins, Cell Transformation, Transgenic, Mice, Models, Gene Order, ras, Neurofibromin 2, Tumor, Nuclear Proteins, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Gene Targeting, Chromosome Deletion, Mitogen-Activated Protein Kinases, Human, Protein Binding, Signal Transduction, Transcriptional Activation, DNA Copy Number Variations, Mice, Transgenic, Models, Biological, Chromosomes, Cell Line, Promoter Regions, Genetic, Cell Line, Tumor, Position-Specific Scoring Matrices, Animals, Humans, Thyroid Neoplasms, Nucleotide Motifs, Protein Kinase Inhibitors, Neoplasm Staging, Neoplastic, Binding Sites, Animal, Biological, Disease Models, Animal, Genes, ras, Gene Expression Regulation, Genes, Drug Resistance, Neoplasm, Disease Models, Neoplasm, Pair 22, Gene Deletion, Transcription Factors
Chromosomes, Human, Pair 22, Drug Resistance, Cell Cycle Proteins, Cell Transformation, Transgenic, Mice, Models, Gene Order, ras, Neurofibromin 2, Tumor, Nuclear Proteins, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Gene Targeting, Chromosome Deletion, Mitogen-Activated Protein Kinases, Human, Protein Binding, Signal Transduction, Transcriptional Activation, DNA Copy Number Variations, Mice, Transgenic, Models, Biological, Chromosomes, Cell Line, Promoter Regions, Genetic, Cell Line, Tumor, Position-Specific Scoring Matrices, Animals, Humans, Thyroid Neoplasms, Nucleotide Motifs, Protein Kinase Inhibitors, Neoplasm Staging, Neoplastic, Binding Sites, Animal, Biological, Disease Models, Animal, Genes, ras, Gene Expression Regulation, Genes, Drug Resistance, Neoplasm, Disease Models, Neoplasm, Pair 22, Gene Deletion, Transcription Factors
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