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|Ref Type||Journal Article|
|Authors||Lu J, Guan S, Zhao Y, Yu Y, Woodfield SE, Zhang H, Yang KL, Bieerkehazhi S, Qi L, Li X, Gu J, Xu X, Jin J, Muscal JA, Yang T, Xu GT, Yang J|
|Title||The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model.|
|Date||2017 Aug 01|
|Abstract Text||Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ALK D1091N||neuroblastoma||sensitive||AZD3463 + Doxorubicin||Preclinical - Cell culture||Actionable||In a preclinical study, AZD3463 treatment enhanced the cytotoxic effects of Adriamycin (doxorubicin) in a neuroblastoma cell line harboring ALK D1091N, demonstrating increased apoptotic activity and decreased cell viability in culture (PMID: 28455243).||28455243|
|ALK D1091N||neuroblastoma||predicted - sensitive||Alectinib||Preclinical - Cell culture||Actionable||In a preclinical study, Alecensa (alectinib) treatment in a neuroblastoma cell line harboring ALK D1091N resulted in decreased cell viability, inhibition of colony formation, and inhibition of Pi3k pathway signaling in culture (PMID: 28455243).||28455243|
|ALK D1091N||neuroblastoma||predicted - sensitive||Alectinib + Doxorubicin||Preclinical - Cell culture||Actionable||In a preclinical study, Alecensa (alectinib) treatment enhanced the cytotoxic effects of Adriamycin (doxorubicin) in a neuroblastoma cell line harboring ALK D1091N, demonstrating increased apoptotic activity and decreased cell viability in culture (PMID: 28455243).||28455243|