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Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells.

Journal article
Authors Diana Lizeth Cervantes-Madrid
Joanna Szydzik
Marcus Borenäs
Mats Bemark
Jean Cui
Ruth H. Palmer
Bengt Hallberg
Published in Scientific reports
Volume 9
Issue 1
Pages 19353
ISSN 2045-2322
Publication year 2019
Published at Institute of Biomedicine, Department of Microbiology and Immunology
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 19353
Language en
Links dx.doi.org/10.1038/s41598-019-55060...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Cell Biology, Molecular medicine, Medical cell biology, Pharmaceutics

Abstract

Neuroblastoma is the most commonly diagnosed extracranial tumor in the first year of life. Approximately 9% of neuroblastoma patients present germline or somatic aberrations in the gene encoding for anaplastic lymphoma kinase (ALK). This increases in high-risk neuroblastomas, which have a 14% frequency of ALK aberrations at the time of diagnosis and show increasing numbers at relapse. Abrogating ALK activity with kinase inhibitors is employed as clinical therapy in malignancies such as non-small cell lung cancer and has shown good results in pediatric inflammatory myofibroblastic tumors and anaplastic large cell lymphomas. A phase I clinical trial of the first generation ALK inhibitor, crizotinib, in neuroblastoma patients showed modest results and suggested that further investigation was needed. Continuous development of ALK inhibitors has resulted in the third generation inhibitor repotrectinib (TPX-0005), which targets the active kinase conformations of ALK, ROS1 and TRK receptors. In the present study we investigated the effects of repotrectinib in a neuroblastoma setting in vitro and in vivo. Neuroblastoma cell lines were treated with repotrectinib to investigate inhibition of ALK and to determine its effect on proliferation. PC12 cells transfected with different ALK mutant variants were used to study the efficacy of repotrectinib to block ALK activation/signaling. The in vivo effect of repotrectinib was also analyzed in a neuroblastoma xenograft model. Our results show that repotrectinib is capable of inhibiting signaling activity of a range of ALK mutant variants found in neuroblastoma patients and importantly it exhibits strong antitumor effects in a xenograft model of neuroblastoma.

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