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 .
Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma. 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.
### Instruction:
            Given the context about compound efficacy for the given treatment mentioned within the input, mentioned the compounds 
            that can co-occur for the mentioned treatment

            ### Input:
            Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma. 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.

            ### Response:
            crizotinib, topotecan, cyclophosphamide
            