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Clin Cancer Res. 2016 Feb 15;22(4):948-60. doi: 10.1158/1078-0432.CCR-15-0379. Epub 2015 Oct 5.

Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma.

Author information

1
Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
2
Division of Oncology, The Center for Biomedical Informatics (CBMi), The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania.
3
Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
4
Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. mosse@chop.edu.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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).

CONCLUSIONS:

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.

PMID:
26438783
PMCID:
PMC4755925
DOI:
10.1158/1078-0432.CCR-15-0379
[Indexed for MEDLINE]
Free PMC Article

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