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|Ref Type||Journal Article|
|Authors||Wood AC, Krytska K, Ryles HT, Infarinato NR, Sano R, Hansel TD, Hart LS, King FJ, Smith TR, Ainscow E, Grandinetti KB, Tuntland T, Kim S, Caponigro G, He YQ, Krupa S, Li N, Harris JL, Mossé YP|
|Title||Dual ALK and CDK4/6 Inhibition Demonstrates Synergy against Neuroblastoma.|
|Abstract Text||Purpose: Anaplastic lymphoma kinase (ALK) is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed an in vitro screen for synergistic drug combinations that target neuroblastomas with mutations in ALK to 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 on in vitro proliferation, cell cycle, viability, caspase activation, and the cyclin D/CDK4/CDK6/RB and pALK signaling networks in cell lines with representative ALK status. We performed in vivo trials 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 with ALK mutations as compared with cell lines lacking mutations or alterations in ALK Compared 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 with ALK-F1174L and F1245C de novo resistance mutations and prevented the emergence of resistance. Murine ribociclib and ceritinib plasma concentrations were unaltered by combination therapy.Conclusions: This preclinical combination drug screen with in vivo validation 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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|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||Ceritinib + Ribociclib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of Zykadia (ceritinib) and Kisqali (ribociclib) synergistically inhibited proliferation and Alk phosphorylation and induced cell cycle arrest in neuroblastoma cell line harboring ALK F1174L in culture, and induced complete tumor regression and increased event-free survival compared to either agent alone (P<0.0001) in a cell line xenograft model (PMID: 27986745).||27986745|
|ALK F1245C||neuroblastoma||sensitive||Ceritinib + Ribociclib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of Zykadia (ceritinib) and Kisqali (ribociclib) inhibited proliferation in a neuroblastoma cell line harboring ALK F1245C in culture, and resulted in enhanced tumor growth inhibition compared to either Zykadia (ceritinib) or Kisqali (ribociclib) alone (P=0.04 and P<0.0001, respectively) and induced complete and sustained tumor regression in a patient-derived xenograft (PDX) model (PMID: 27986745).||27986745|
|ALK R1275Q||neuroblastoma||sensitive||Ceritinib + Ribociclib||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of Zykadia (ceritinib) and Kisqali (ribociclib) synergistically inhibited proliferation and Alk phosphorylation and induced cell cycle arrest in neuroblastoma cell lines harboring ALK R1275Q in culture (PMID: 27986745).||27986745|
|ALK del exon2 ALK del exon3 ALK amp||neuroblastoma||sensitive||Ceritinib + Ribociclib||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of Zykadia (ceritinib) and Kisqali (ribociclib) inhibited proliferation in a neuroblastoma cell line harboring a deletion of ALK exons 2 and 3 and ALK amplification in culture (PMID: 27986745).||27986745|