دورية أكاديمية
أعرض في EDS

Targeting ALK in pediatric RMS does not induce antitumor activity in vivo.

التفاصيل البيبلوغرافية
العنوان: Targeting ALK in pediatric RMS does not induce antitumor activity in vivo.
المؤلفون: Wierdl M; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA., Tsurkan L; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA., Chi L; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA., Hatfield MJ; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA., Tollemar V; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA., Bradley C; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA., Chen X; Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA., Qu C; Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA., Potter PM; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-2794, USA. phil.potter@stjude.org.
المصدر: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2018 Aug; Vol. 82 (2), pp. 251-263. Date of Electronic Publication: 2018 May 31.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7806519 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0843 (Electronic) Linking ISSN: 03445704 NLM ISO Abbreviation: Cancer Chemother Pharmacol
أسماء مطبوعة: Publication: Berlin : Springer Verlag
Original Publication: Berlin, New York, Springer International.
مواضيع طبية MeSH: Anaplastic Lymphoma Kinase/*antagonists & inhibitors , Anaplastic Lymphoma Kinase/*biosynthesis , Rhabdomyosarcoma/*drug therapy , Rhabdomyosarcoma/*enzymology, Anaplastic Lymphoma Kinase/genetics ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Cell Growth Processes/drug effects ; Cell Line, Tumor ; Crizotinib/administration & dosage ; Crizotinib/pharmacology ; Cyclophosphamide/administration & dosage ; Dactinomycin/administration & dosage ; Drug Interactions ; Humans ; Mice ; Mice, Nude ; Molecular Targeted Therapy ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/pharmacology ; Protein-Tyrosine Kinases/biosynthesis ; Protein-Tyrosine Kinases/genetics ; Proto-Oncogene Proteins/biosynthesis ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins c-met/biosynthesis ; Proto-Oncogene Proteins c-met/genetics ; Pyrimidines/pharmacology ; RNA, Small Interfering/administration & dosage ; RNA, Small Interfering/genetics ; Rhabdomyosarcoma/genetics ; Transfection ; Vincristine/administration & dosage ; Xenograft Model Antitumor Assays
مستخلص: 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.
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معلومات مُعتمدة: P30 CA021765 United States CA NCI NIH HHS; R25 CA023944 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: ALK; ALK inhibitors; Crizotinib; Patient-derived xenografts; Rhabdomyosarcoma
المشرفين على المادة: 0 (NVP-TAE684)
0 (Protein Kinase Inhibitors)
0 (Proto-Oncogene Proteins)
0 (Pyrimidines)
0 (RNA, Small Interfering)
1CC1JFE158 (Dactinomycin)
53AH36668S (Crizotinib)
5J49Q6B70F (Vincristine)
8N3DW7272P (Cyclophosphamide)
EC 2.7.10.1 (ALK protein, human)
EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
EC 2.7.10.1 (MET protein, human)
EC 2.7.10.1 (Protein-Tyrosine Kinases)
EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
EC 2.7.10.1 (ROS1 protein, human)
تواريخ الأحداث: Date Created: 20180602 Date Completed: 20190801 Latest Revision: 20240328
رمز التحديث: 20240329
مُعرف محوري في PubMed: PMC6054567
DOI: 10.1007/s00280-018-3615-7
PMID: 29855693
قاعدة البيانات: MEDLINE
الوصف
تدمد:1432-0843
DOI:10.1007/s00280-018-3615-7