Identification of response signatures for tankyrase inhibitor treatment in tumor cell lines.

Autor:	Mygland L; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317 Oslo, Norway., Brinch SA; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317 Oslo, Norway., Strand MF; School of Health Sciences, Kristiania University College, P.O. Box 1190 Sentrum, 0107 Oslo, Norway., Olsen PA; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317 Oslo, Norway., Aizenshtadt A; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317 Oslo, Norway., Lund K; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway., Solberg NT; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway., Lycke M; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway., Thorvaldsen TE; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, 0379 Oslo, Norway., Espada S; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317 Oslo, Norway., Misaghian D; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway., Page CM; Center for Fertility and Health, Norwegian Institute of Public Health, P.O. Box 222 Skøyen, 0213 Oslo, Norway.; Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway., Agafonov O; Bioinformatics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Ullernchausseen 70, 0379 Oslo, Norway., Nygård S; Department of Informatics, University of Oslo, P.O. box 080 Blindern, 0316 Oslo, Norway., Chi NW; Endocrine Service, VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA 92161, USA., Lin E; Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Tan J; Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Yu Y; Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Costa M; Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Krauss S; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317 Oslo, Norway., Waaler J; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317 Oslo, Norway.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2021 Jul 01; Vol. 24 (7), pp. 102807. Date of Electronic Publication: 2021 Jul 01 (Print Publication: 2021).
DOI:	10.1016/j.isci.2021.102807
Abstrakt:	Small-molecule tankyrase 1 and tankyrase 2 (TNKS1/2) inhibitors are effective antitumor agents in selected tumor cell lines and mouse models. Here, we characterized the response signatures and the in-depth mechanisms for the antiproliferative effect of tankyrase inhibition (TNKSi). The TNKS1/2-specific inhibitor G007-LK was used to screen 537 human tumor cell lines and a panel of particularly TNKSi-sensitive tumor cell lines was identified. Transcriptome, proteome, and bioinformatic analyses revealed the overall TNKSi-induced response signatures in the selected panel. TNKSi-mediated inhibition of wingless-type mammary tumor virus integration site/β-catenin, yes-associated protein 1 (YAP), and phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT signaling was validated and correlated with lost expression of the key oncogene MYC and impaired cell growth. Moreover, we show that TNKSi induces accumulation of TNKS1/2-containing β - catenin degradasomes functioning as core complexes interacting with YAP and angiomotin proteins during attenuation of YAP signaling. These findings provide a contextual and mechanistic framework for using TNKSi in anticancer treatment that warrants further comprehensive preclinical and clinical evaluations. (© 2021 The Authors.)
Databáze:	MEDLINE
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