title: Inhibition of Axl improves the targeted therapy against ALK-mutated neuroblastoma.
abstract: Neuroblastoma (NB) patients harboring mutated ALK can be expected to potentially benefit from targeted therapy based on ALK tyrosine kinase inhibitor (TKI), such as crizotinib and ceritinib. However, the effect of the treatment varies with different individuals, although with the same genic changes. Axl receptor tyrosine kinase is expressed in a variety of human cancers, but little data are reported in NB, particularly in which carrying mutated ALK. In this study, we focus on the roles of Axl in ALK-mutated NB for investigating rational therapeutic strategy. We found that Axl is expressed in ALK-positive NB tissues and cell lines, and could be effectively activated by its ligand GAS6. Ligand-dependent Axl activation obviously rescued crizotinib-mediated suppression of cell proliferation in ALK-mutated NB cells. Genetic inhibition of Axl with specific small interfering RNA markedly increased the sensitivity of cells to ALK-TKIs. Furthermore, a small-molecule inhibitor of Axl significantly enhanced ALK-targeted therapy, as an increased frequency of apoptosis was observed in NB cells co-expressing ALK and Axl. Taken together, our results demonstrated that activation of Axl could lead to insensitivity to ALK inhibitors, and dual inhibition of ALK and Axl might be a potential therapeutic strategy against ALK-mutated NB.
authors.affiliation: Department of Neurology, Sichuan Medical Science Institute & Sichuan Provincial Hospital, Chengdu 610072, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Radiotherapy, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 201620, China.
authors.forename: Hongling
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Burn and Plastic Surgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, China. Electronic address: sunfanqi2010@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001567:Benzocycloheptenes / Q000008:administration & dosage / Q000494:pharmacology*; D000077547:Crizotinib; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D001567:Benzocycloheptenes; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D014230:Triazoles; C548378:bemcentinib; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase
keywords: ALK; Axl; Neuroblastoma; Small-molecule inhibitor; Targeted therapy