Crizotinib Synergizes with Chemotherapy in Preclinical Models of Neuroblastoma

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 multi-agent therapy for ALK-aberrant neuroblastoma patients.

Dual ALK and CDK4/6 Inhibition Demonstrates Synergy against Neuroblastoma

“…TP53 activation may contribute to synergy when ALK inhibitors are combined with cytotoxic chemotherapy(37), and TP53 inactivation has been associated with neuroblastoma relapse and multidrug resistance(36). Therefore, we sought to determine if combination Ceritinib and Ribociclib acted in a p53 independent manner.…”

Cytotoxic activity of difluoromethylornithine compared with fenretinide in neuroblastoma cell lines

“…This study was undertaken to compare the direct anti‐neuroblastoma effect of two well‐tolerated agents (DFMO and fenretinide) that have been considered for addition to the maintenance phase of therapy for high‐risk neuroblastoma. The panel of neuroblastoma cell lines we employed represents high‐risk neuroblastoma and included cell lines that have MYCN genomic amplification, the alternate lengthening of telomeres (ALT) phenotype, and anaplastic lymphoma kinase ( ALK ) mutations . DFMO was used to treat neuroblastoma cell lines at a concentration comparable with maximal levels achieved in a neuroblastoma maintenance therapy clinical trial (NCT01586260 and NCT02679144).…”

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

“…An increasing number of targeted agents are now entering early phase paediatric trials including the lead Novartis MDM2 antagonist, HDM-201, as part of the Next Generation Personalised Neuroblastoma Therapy (NEPENTHE) trial (NCT02780128) and the dual MDM2/MDMX inhibitor ALRN-6924 (NCT03654716). Additionally, Alisertib (Aurora kinase A) and Crizotinib (ALK) have progressed to Phase I/II trials in combination with chemotherapy in neuroblastoma patients [38][39][40] and the benefit of incorporating Crizotinib to upfront standard therapy for patients with newly diagnosed high-risk neuroblastoma will be evaluated in an upcoming Phase III trial (NCT03126916). Full results from the recently completed Phase I trial of RO6839921 in adults with advanced solid tumours and AML are pending (NCT02098967).…”