A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma

Berglind O. Einarsdottir, Joakim Karlsson, Elin M.V. Söderberg, Mattias F. Lindberg, Elisa Funck-Brentano, Henrik Jespersen, Siggeir F. Brynjolfsson, Roger Olofsson Bagge, Louise Carstam, Martin Scobie, Tobias Koolmeister, Olof Wallner, Ulrika Stierner, Ulrika Warpman Berglund, Lars Ny, Lisa M. Nilsson, Erik Larsson, Thomas Helleday, Jonas A. Nilsson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.

Original languageEnglish
Article number810
JournalCell Death and Disease
Issue number8
Publication statusPublished - 1 Aug 2018

Bibliographical note

Funding Information:
We wish to thank Sofia Stenqvist for the assistance with animal experiments. This work was supported by the Swedish Cancer Society and the Swedish Research Council (to J.A.N., T.H., and E.L.), the Knut and Alice Wallenberg Foundation (to J.A.N. and T.H.) and the Region Västra Götaland (Sahlgrenska University Hospital, Gothenburg), the IngaBritt and Arne Lundberg Foundation, BioCARE—a National Strategic Cancer Research Program at University of Gothenburg, the Lion’s Cancer Foundation West and Familjen Erling Perssons Stiftelse (to J.A.N.), the Swedish Foundation for Strategic Research (T.H.), the Assar Gabrielsson Foundation, the W&M Lundgren Foundation and Sahlgrenska Universitetssjukhusets stiftelser (Sahlgrenska University Hospital, Gothenburg) (to B.O.E., E.M.V.S. and M.F.L.), and the European Academy of Dermatology and Venereology and the Fondation Nuovo Soldati (to E.F.-B.).

Publisher Copyright:
© 2018, The Author(s).


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