Reference Detail

Ref Type

Journal Article

PMID

(26438783)

Authors

Krytska K, Ryles HT, Sano R, Raman P, Infarinato NR, Hansel TD, Makena MR, Song MM, Reynolds CP, Mossé YP

Title

Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	22	4	2016 Feb 15	948-60	Clin Cancer Res

URL

Abstract Text

The presence of an ALK aberration correlates with inferior survival for patients with high-risk neuroblastoma. The emergence of ALK inhibitors such as crizotinib has provided novel treatment opportunities. However, certain ALK mutations result in de novo crizotinib resistance, and a phase I trial of crizotinib showed a lack of response in patients harboring those ALK mutations. Thus, understanding mechanisms of resistance and defining circumvention strategies for the clinic is critical.The sensitivity of human neuroblastoma-derived cell lines, cell line-derived, and patient-derived xenograft (PDX) models with varying ALK statuses to crizotinib combined with topotecan and cyclophosphamide (topo/cyclo) was examined. Cultured cells and xenografts were evaluated for effects of these drugs on proliferation, signaling, and cell death, and assessment of synergy.In neuroblastoma murine xenografts harboring the most common ALK mutations, including those mutations associated with resistance to crizotinib (but not in those with wild-type ALK), crizotinib combined with topo/cyclo enhanced tumor responses and mouse event-free survival. Crizotinib + topo/cyclo showed synergistic cytotoxicity and higher caspase-dependent apoptosis than crizotinib or topo/cyclo alone in neuroblastoma cell lines with ALK aberrations (mutation or amplification).Combining crizotinib with chemotherapeutic agents commonly used in treating newly diagnosed patients with high-risk neuroblastoma restores sensitivity in preclinical models harboring both sensitive ALK aberrations and de novo-resistant ALK mutations. These data support clinical testing of crizotinib and conventional chemotherapy with the goal of integrating ALK inhibition into multiagent therapy for ALK-aberrant neuroblastoma patients.

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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 wild-type TP53 wild-type	neuroblastoma	no benefit	Crizotinib + Cyclophosphamide + Topotecan	Preclinical - Cell culture	Actionable	In a preclinical study, Xalkori (crizotinib) did not demonstrate synergy with the combination of Topotecan and Cytoxan (cyclophosphamide) on growth inhibition in neuroblastoma cell lines harboring wild-tpye Alk and wild-type TP53 in culture (PMID: 26438783).	26438783
ALK R1275Q	neuroblastoma	sensitive	Crizotinib + Cyclophosphamide + Topotecan	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Xalkori (crizotinib), Topotecan, and Cytoxan (cyclophosphamide) synergized to sustain tumor regression in human neuroblastoma cell line xenograft models harboring ALK R1275Q and wild-type TP53 (PMID: 26438783).	26438783
ALK amp TP53 wild-type	neuroblastoma	sensitive	Crizotinib + Cyclophosphamide + Topotecan	Preclinical - Cell culture	Actionable	In a preclinical study, Xalkori (crizotinib) demonstrated synergy with the combination of Topotecan and Cytoxan (cyclophosphamide) in neuroblastoma cell lines harboring Alk amplification and functional TP53, resulting in growth inhibition in culture (PMID: 26438783).	26438783
ALK wild-type TP53 H168R	neuroblastoma	no benefit	Crizotinib + Cyclophosphamide + Topotecan	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Xalkori (crizotinib) did not improve the effect of Topotecan and Cytoxan (cyclophosphamide) on tumor growth suppression in xenograft models of a human neuroblastoma cell line harboring wild-type ALK and TP53 H168R (PMID: 26438783).	26438783
ALK act mut TP53 wild-type	neuroblastoma	predicted - sensitive	Crizotinib + Cyclophosphamide + Topotecan	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Xalkori (crizotinib), Topotecan, and Cytoxan (cyclophosphamide) synergized to delay tumor growth in xenograft models of a human neuroblastoma cell line harboring constitutively phosphorylated wild-type Alk and wild-type TP53 (PMID: 26438783).	26438783
ALK wild-type TP53 C176F	neuroblastoma	no benefit	Crizotinib + Cyclophosphamide + Topotecan	Preclinical - Cell culture	Actionable	In a preclinical study, Xalkori (crizotinib) did not demonstrate synergy with the combination of Topotecan and Cytoxan (cyclophosphamide) on growth inhibition in neuroblastoma cell lines harboring wild-tpye Alk and TP53 C176F in culture (PMID: 26438783).	26438783
ALK F1174L TP53 wild-type	neuroblastoma	sensitive	Crizotinib + Cyclophosphamide + Topotecan	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Xalkori (crizotinib), Topotecan, and Cytoxan (cyclophosphamide) synergized to sustain tumor regression in xenograft models of a crizotinib-resistant human neuroblastoma cell line harboring ALK F1174L and wild-type TP53 (PMID: 26438783).	26438783
ALK wild-type TP53 mut	neuroblastoma	no benefit	Crizotinib + Cyclophosphamide + Topotecan	Preclinical - Cell culture	Actionable	In a preclinical study, Xalkori (crizotinib) did not demonstrate synergy with the combination of Topotecan and Cytoxan (cyclophosphamide) on growth inhibition in neuroblastoma cell lines harboring wild-tpye Alk and TP53 mutations in culture (PMID: 26438783).	26438783
ALK wild-type TP53 P177T	neuroblastoma	no benefit	Crizotinib + Cyclophosphamide + Topotecan	Preclinical - Cell culture	Actionable	In a preclinical study, Xalkori (crizotinib) did not demonstrate synergy with the combination of Topotecan and Cytoxan (cyclophosphamide) on growth inhibition in neuroblastoma cell lines harboring wild-tpye Alk and TP53 P177T in culture (PMID: 26438783).	26438783
ALK mut TP53 wild-type	neuroblastoma	sensitive	Crizotinib + Cyclophosphamide + Topotecan	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Xalkori (crizotinib) demonstrated synergy with the combination of Topotecan and Cytoxan (cyclophosphamide) in patient-derived neuroblastoma cell lines harboring Alk mutations and functional TP53, resulting in growth inhibition in culture and tumor regression in animal models (PMID: 26438783).	26438783
ALK F1245C TP53 wild-type	neuroblastoma	sensitive	Crizotinib + Cyclophosphamide + Topotecan	Preclinical - Pdx	Actionable	In a preclinical study, Xalkori (crizotinib) worked synergistically with Topotecan and Cytoxan (cyclophosphamide), resulting in sustained tumor regression in crizotinib-resistant neuroblastoma PDX models harboring ALK F1245C and wild-type Tp53 (PMID: 26438783).	26438783