Targeting ALK in pediatric RMS does not induce antitumor activity in vivo
| Autor: | Monika Wierdl, Cori Bradley, Chunxu Qu, Philip M. Potter, M. Jason Hatfield, Xiang Chen, Viktor Tollemar, Lyudmila Tsurkan, Liying Chi |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Vincristine Mice Nude Cell Growth Processes Toxicology Transfection Article 03 medical and health sciences Mice 0302 clinical medicine Crizotinib In vivo hemic and lymphatic diseases Cell Line Tumor Proto-Oncogene Proteins Antineoplastic Combined Chemotherapy Protocols Rhabdomyosarcoma Medicine Anaplastic lymphoma kinase Animals Humans Pharmacology (medical) Anaplastic Lymphoma Kinase Drug Interactions Molecular Targeted Therapy RNA Small Interfering Anaplastic large-cell lymphoma Cyclophosphamide Protein Kinase Inhibitors Pharmacology business.industry Kinase Cell growth Protein-Tyrosine Kinases Proto-Oncogene Proteins c-met medicine.disease Xenograft Model Antitumor Assays 030104 developmental biology Pyrimidines Oncology 030220 oncology & carcinogenesis Cancer research Dactinomycin business medicine.drug |
| Popis: | PURPOSE: The anaplastic lymphoma kinase (ALK) has been demonstrated to be a valid clinical target in diseases such as anaplastic large cell lymphoma and non-small cell lung cancer. Recent studies have indicated that ALK is overexpressed in pediatric rhabdomyosarcoma (RMS) and hence we hypothesized that this kinase may be a suitable candidate for therapeutic intervention in this tumor. METHODS: We evaluated the expression of ALK in a panel of pediatric RMS cell lines and patient-derived xenografts (PDX), and sensitivity to ALK inhibitors was assessed both in vitro and in vivo. RESULTS: Essentially all RMS lines were sensitive to crizotinib, NVP-TAE684 or LDK-378 in vitro, and molecular analyses demonstrated inhibition of RMS cell proliferation following siRNA-mediated reduction of ALK expression. However, in vivo PDX studies using ALK kinase inhibitors demonstrated no antitumor activity when used as single agents or when combined with standard of care therapy (vincristine, actinomycin D and cyclophosphamide). More alarmingly however, crizotinib actually accelerated the growth of these tumors in vivo. CONCLUSIONS: While ALK appears to be a relevant target in RMS in vitro, targeting this kinase in vivo yields no therapeutic efficacy, warranting extreme caution when considering the use of these agents in pediatric RMS patients. |
| Databáze: | OpenAIRE |
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