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

Journal article
Authors Berglind Osk Einarsdottir
Joakim Karlsson
Elin Söderberg
Mattias F Lindberg
Elisa Funck-Brentano
Henrik Jespersen
Siggeir Fannar Brynjólfsson
Roger Olofsson Bagge
Louise Carstam
M. Scobie
T. Koolmeister
O. Wallner
Ulrika Stierner
U. W. Berglund
Lars Ny
Lisa M Nilsson
Erik Larsson
T. Helleday
Jonas A Nilsson
Published in Cell Death & Disease
Volume 9
Issue 8
ISSN 2041-4889
Publication year 2018
Published at Institute of Clinical Sciences, Department of Surgery
Institute of Clinical Sciences, Department of Oncology
Sahlgrenska Cancer Center
Institute of Biomedicine, Department of Microbiology and Immunology
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Language en
Links dx.doi.org/10.1038/s41419-018-0865-...
Keywords cancer-cell survival, multidrug-resistance, p-glycoprotein, mth1, inhibitors, expression, annotation, guideline, exome, model, Cell Biology
Subject categories Cell and Molecular Biology, Cancer and Oncology

Abstract

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.

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