Funding
Cancer Research UK (CRUK)
CHILDREN with CANCER UK
Neuroblastoma UK
Niamh's Next Step
Children Cancer North
Newcastle National Institute for Health Research Biomedical Research Centre
Little Princess Trust (LPT)
Annenberg Foundation (The Annenberg Foundation)
Association Hubert Gouin Enfance et Cancer (Hubert Gouin Association)
Federation Enfants Cancer Santé
Society française de lutte contre les cancers et les leucémies de i'enfant et l'adolescent
Les Bagouz a Manon
Les Amis de Claire
Fondation ARC pour le recherche contre le cancer
SiRIC/INCa
PHRC
Institut Curie Equipex
Institut Curie France Genomique Consortium
Canceropôle PACA (Canceropole PACA)
IMI2 ITCC-P4
Parrainage medecin-chercheur
ARTICLE ABSTRACT
ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%–2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway.
We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX).
Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth.
In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.
