Reference Detail

Ref Type

Journal Article

PMID

(26786851)

Authors

Wang Y, Wang L, Guan S, Cao W, Wang H, Chen Z, Zhao Y, Yu Y, Zhang H, Pang JC, Huang SL, Akiyama Y, Yang Y, Sun W, Xu X, Shi Y, Kim ES, Muscal JA, Lu F, Yang J

Title

Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Scientific reports	6		2016 Jan 20	19423	Sci Rep

URL

Abstract Text

ALK receptor tyrosine kinase has been shown to be a therapeutic target in neuroblastoma. Germline ALK activating mutations are responsible for the majority of hereditary neuroblastoma and somatic ALK activating mutations are also frequently observed in sporadic cases of advanced NB. Crizotinib, a first-line therapy in the treatment of advanced non-small cell lung cancer (NSCLC) harboring ALK rearrangements, demonstrates striking efficacy against ALK-rearranged NB. However, crizotinib fails to effectively inhibit the activity of ALK when activating mutations are present within its kinase domain, as with the F1174L mutation. Here we show that a new ALK inhibitor AZD3463 effectively suppressed the proliferation of NB cell lines with wild type ALK (WT) as well as ALK activating mutations (F1174L and D1091N) by blocking the ALK-mediated PI3K/AKT/mTOR pathway and ultimately induced apoptosis and autophagy. In addition, AZD3463 enhanced the cytotoxic effects of doxorubicin on NB cells. AZD3463 also exhibited significant therapeutic efficacy on the growth of the NB tumors with WT and F1174L activating mutation ALK in orthotopic xenograft mouse models. These results indicate that AZD3463 is a promising therapeutic agent in the treatment of NB.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
AZD3463	AZD3463	7	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AZD3463		AZD-3463\|AZD 3463	ALK Inhibitor 32 IGF-1R Inhibitor 17 ROS1 Inhibitor 20	AZD3463 inhibits IGF1R and ALK, including wild-type and mutant ALK, and has additional activity against ROS1 fusions, which decreases downstream signaling resulting in reduced tumor cell growth (PMID: 26786851, PMID: 26372962, PMID: 32698744, PMID: 32355780).

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 F1174L	neuroblastoma	sensitive	AZD3463	Preclinical - Cell line xenograft	Actionable	In a preclinical study, AZD3463 inhibited growth of neuroblastoma cells harboring ALK F1174L in culture, resulted in near complete tumor regression in cell line xenograft models (PMID: 26786851).	26786851
ALK D1091N	neuroblastoma	sensitive	AZD3463	Preclinical - Cell culture	Actionable	In a preclinical study, AZD3463 treatment in a neuroblastoma cell line harboring ALK D1091N resulted in inhibition of colony formation, repression of Pi3k signaling, and induction of apoptosis in culture (PMID: 26786851).	26786851