title: DualALKandCDK4/6Inhibition Demonstrates Synergy against Neuroblastoma.
abstract: Purpose:Anaplastic lymphoma kinase (ALK) is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed anin vitroscreen for synergistic drug combinations that target neuroblastomas with mutations inALKto determine whether drug combinations could enhance antitumor efficacy.Experimental Design:We screened combinations of eight molecularly targeted agents against 17 comprehensively characterized human neuroblastoma-derived cell lines. We investigated the combination of ceritinib and ribociclib onin vitroproliferation, cell cycle, viability, caspase activation, and the cyclin D/CDK4/CDK6/RB and pALK signaling networks in cell lines with representative ALK status. We performedin vivotrials in CB17 SCID mice bearing conventional and patient-derived xenograft models comparing ceritinib alone, ribociclib alone, and the combination, with plasma pharmacokinetics to evaluate for drug-drug interactions.Results:The combination of ribociclib, a dual inhibitor of cyclin-dependent kinase (CDK) 4 and 6, and the ALK inhibitor ceritinib demonstrated higher cytotoxicity (P= 0.008) and synergy scores (P= 0.006) in cell lines withALKmutations as compared with cell lines lacking mutations or alterations inALKCompared with either drug alone, combination therapy enhanced growth inhibition, cell-cycle arrest, and caspase-independent cell death. Combination therapy achieved complete regressions in neuroblastoma xenografts withALK-F1174L and F1245Cde novoresistance mutations and prevented the emergence of resistance. Murine ribociclib and ceritinib plasma concentrations were unaltered by combination therapy.Conclusions:This preclinical combination drug screen within vivovalidation has provided the rationale for a first-in-children trial of combination ceritinib and ribociclib in a molecularly selected pediatric population.Clin Cancer Res; 23(11); 2856-68. ©2016 AACR.
authors.affiliation: Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Wood
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Kateryna
authors.initials: K
authors.lastname: Krytska
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Hannah T
authors.initials: HT
authors.lastname: Ryles
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Infarinato
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Renata
authors.initials: R
authors.lastname: Sano
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Theodore D
authors.initials: TD
authors.lastname: Hansel
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Hart
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: King
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Smith
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Edward
authors.initials: E
authors.lastname: Ainscow
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Grandinetti
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.affiliation: Novartis Institutes of Biomedical Research, Cambridge, Massachusetts.
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Kim
authors.affiliation: Novartis Institutes of Biomedical Research, Cambridge, Massachusetts.
authors.forename: Giordano
authors.initials: G
authors.lastname: Caponigro
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: You Qun
authors.initials: YQ
authors.lastname: He
authors.affiliation: Novartis Institutes of Biomedical Research, Cambridge, Massachusetts.
authors.forename: Shiva
authors.initials: S
authors.lastname: Krupa
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Nanxin
authors.initials: N
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harris
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. mosse@email.chop.edu.
authors.forename: Yaël P
authors.initials: YP
authors.lastname: Mossé
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056741:Cyclin D / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011687:Purines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000008:administration & dosage; D013450:Sulfones / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D056741:Cyclin D; D011687:Purines; D011743:Pyrimidines; D016160:Retinoblastoma Protein; D054852:Small Molecule Libraries; D013450:Sulfones; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C586847:ceritinib; C000589651:ribociclib