Identification of response signatures for tankyrase inhibitor treatment in tumor cell lines
Line Mygland,
Shoshy Alam Brinch,
Martin Frank Strand,
Petter Angell Olsen,
Aleksandra Aizenshtadt,
Kaja Lund,
Nina Therese Solberg,
Max Lycke,
Tor Espen Thorvaldsen,
Sandra Espada,
Dorna Misaghian,
Christian M. Page,
Oleg Agafonov,
Ståle Nygård,
Nai-Wen Chi,
Eva Lin,
Jenille Tan,
Yihong Yu,
Mike Costa,
Stefan Krauss,
Jo Waaler
Affiliations
Line Mygland
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
Shoshy Alam Brinch
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
Martin Frank Strand
School of Health Sciences, Kristiania University College, P.O. Box 1190 Sentrum, 0107 Oslo, Norway
Petter Angell Olsen
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
Aleksandra Aizenshtadt
Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317 Oslo, Norway
Kaja Lund
Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway
Nina Therese Solberg
Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway
Max Lycke
Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway
Tor Espen Thorvaldsen
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, 0379 Oslo, Norway
Sandra Espada
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
Dorna Misaghian
Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway
Christian M. Page
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
Oleg Agafonov
Bioinformatics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Ullernchausseen 70, 0379 Oslo, Norway
Ståle Nygård
Department of Informatics, University of Oslo, P.O. box 080 Blindern, 0316 Oslo, Norway
Nai-Wen Chi
Endocrine Service, VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA 92161, USA
Eva Lin
Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Jenille Tan
Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Yihong Yu
Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Mike Costa
Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
Stefan Krauss
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
Jo Waaler
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; Corresponding author
Summary: 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.
