title: Tankyrase Inhibitor Sensitizes Lung Cancer Cells to Endothelial Growth Factor Receptor (EGFR) Inhibition via Stabilizing Angiomotins and Inhibiting YAP Signaling.
abstract: YAP signaling pathway plays critical roles in tissue homeostasis, and aberrant activation of YAP signaling has been implicated in cancers. To identify tractable targets of YAP pathway, we have performed a pathway-based pooled CRISPR screen and identified tankyrase and its associated E3 ligase RNF146 as positive regulators of YAP signaling. Genetic ablation or pharmacological inhibition of tankyrase prominently suppresses YAP activity and YAP target gene expression. Using a proteomic approach, we have identified angiomotin family proteins, which are known negative regulators of YAP signaling, as novel tankyrase substrates. Inhibition of tankyrase or depletion of RNF146 stabilizes angiomotins. Angiomotins physically interact with tankyrase through a highly conserved motif at their N terminus, and mutation of this motif leads to their stabilization. Tankyrase inhibitor-induced stabilization of angiomotins reduces YAP nuclear translocation and decreases downstream YAP signaling. We have further shown that knock-out of YAP sensitizes non-small cell lung cancer to EGFR inhibitor Erlotinib. Tankyrase inhibitor, but not porcupine inhibitor, which blocks Wnt secretion, enhances growth inhibitory activity of Erlotinib. This activity is mediated by YAP inhibition and not Wnt/β-catenin inhibition. Our data suggest that tankyrase inhibition could serve as a novel strategy to suppress YAP signaling for combinatorial targeted therapy.
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: Johnny
authors.initials: J
authors.lastname: Castillo
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: Zinger
authors.initials: Z
authors.lastname: Yang
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: Gregory
authors.initials: G
authors.lastname: McAllister
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: Alicia
authors.initials: A
authors.lastname: Lindeman
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: John
authors.initials: J
authors.lastname: Reece-Hoyes
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: John
authors.initials: J
authors.lastname: Tallarico
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: Carsten
authors.initials: C
authors.lastname: Russ
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: Greg
authors.initials: G
authors.lastname: Hoffman
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, Washington 98195.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Xu
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and.
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.affiliation: From the Department of Developmental and Molecular Pathways, Novartis Institute of Biomedical Research, Cambridge, Massachusetts 02139 and feng.cong@novartis.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Cong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000091082:Angiomotins; D000970:Antineoplastic Agents / Q000494:pharmacology; D064113:CRISPR-Cas Systems; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000091082:Angiomotins; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D038501:Tankyrases; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000091102:YAP-Signaling Proteins; C423985:AMOT protein, human; C088374:YAP1 protein, human; C561932:RNF146 protein, human; C437334:TNKS2 protein, human; C418109:TNKS protein, human; C512478:EGFR protein, human
keywords: CRISPR/Cas; drug resistance; functional genomics; protein degradation; signal transduction; yes-associated protein (YAP)