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

doi:10.1016/j.isci.2021.102807

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

iScience. 2021 Jul 1;24(7):102807. doi: 10.1016/j.isci.2021.102807. eCollection 2021 Jul 23.

Authors

Line Mygland^{1

2}, Shoshy Alam Brinch^{1

2}, Martin Frank Strand³, Petter Angell Olsen^{1

2}, Aleksandra Aizenshtadt², Kaja Lund¹, Nina Therese Solberg¹, Max Lycke¹, Tor Espen Thorvaldsen⁴, Sandra Espada^{1

2}, Dorna Misaghian¹, Christian M Page^{5

6}, Oleg Agafonov⁷, Ståle Nygård⁸, Nai-Wen Chi⁹, Eva Lin¹⁰, Jenille Tan¹⁰, Yihong Yu¹⁰, Mike Costa¹⁰, Stefan Krauss^{1

2}, Jo Waaler^{1

2}

Affiliations

¹ Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950 Nydalen, Oslo 0424, Norway.
² Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110 Blindern, 0317 Oslo, Norway.
³ School of Health Sciences, Kristiania University College, P.O. Box 1190 Sentrum, 0107 Oslo, Norway.
⁴ Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, 0379 Oslo, Norway.
⁵ Center for Fertility and Health, Norwegian Institute of Public Health, P.O. Box 222 Skøyen, 0213 Oslo, Norway.
⁶ Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway.
⁷ Bioinformatics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Ullernchausseen 70, 0379 Oslo, Norway.
⁸ Department of Informatics, University of Oslo, P.O. box 080 Blindern, 0316 Oslo, Norway.
⁹ Endocrine Service, VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA 92161, USA.
¹⁰ Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Abstract

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.

Keywords: Cancer; Proteomics; Transcriptomics.