title: Smac mimetic LCL161 supports neuroblastoma chemotherapy in a drug class-dependent manner and synergistically interacts with ALK inhibitor TAE684 in cells with ALK mutation F1174L.
abstract: Neuroblastoma is the most common extracranial solid tumor during infancy and childhood.Outcome of high-risk and late-stage disease remains poor despite intensive treatment regimens.Suppressing inhibitor of apoptosis proteins (IAPs) using Smac mimetics (SM) significantly sensitizes neuroblastoma (NB) cells for chemotherapy, however strongly dependent on the cytotoxic drug combined with SM.Therefore, a systematic analysis of the impact of SM in combination with different classes of chemotherapeutics was of crucial importance. Treatment of NB cell lines with SM LCL161 and vinca alkaloids revealed a strong synergistic inhibition of proliferation and significant induction of apoptosis in virtually all established and de novo NB cell lines (n=8).In contrast, combination of anthracyclines or topoisomerase inhibitors with LCL161 showed a synergism for single drugs and/or cell lines only.Furthermore, we could show that insensibility to LCL161-mediated sensitization for chemotherapeutics is associated with aberrant activation of anaplastic lymphoma kinase (ALK) by common mutation F1174L. Inhibition of ALK using TAE684 is able to overcome this resistance in a synergistic fashion, a finding that could be highly relevant for improvement of neuroblastoma therapy.
authors.affiliation: Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Safiullah
authors.initials: S
authors.lastname: Najem
authors.affiliation: Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Doerte
authors.initials: D
authors.lastname: Langemann
authors.affiliation: Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Appl
authors.affiliation: Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Trochimiuk
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hundsdoerfer
authors.affiliation: Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Reinshagen
authors.affiliation: Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Eschenburg
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D006801:Humans; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000037:antagonists & inhibitors*; D020794:Receptor Protein-Tyrosine Kinases; D013844:Thiazoles / Q000378:metabolism*
chemical_list: C574246:LCL161; C516714:NVP-TAE684; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: LCL161; anaplastic lymphoma kinase; chemotherapy; neuroblastoma; smac mimetics