title: Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis.
abstract: 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.
authors.affiliation: Department of Microbiology, Peking University Health Science Center, Beijing 100191, China.|Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Acupuncture, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Guan
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.
authors.forename: Wenming
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Hepatopancreatobiliary Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Zhenghu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Pang
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Sophia L
authors.initials: SL
authors.lastname: Huang
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yo
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Pediatric Surgery, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Sun
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Division of Pediatric Surgery, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Pediatric Surgery, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Muscal
authors.affiliation: Department of Microbiology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Fengmin
authors.initials: F
authors.lastname: Lu
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077547:Crizotinib; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000077548:Anaplastic Lymphoma Kinase; D000077547:Crizotinib; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011725:Pyridines; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C000626173:ALK protein, human; C000626174:Alk protein, mouse