Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models

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-aber...

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Published in:Clinical cancer research 2023-04, Vol.29 (7), p.1317-1331
Main Authors: Tucker, Elizabeth R, Jiménez, Irene, Chen, Lindi, Bellini, Angela, Gorrini, Chiara, Calton, Elizabeth, Gao, Qiong, Che, Harvey, Poon, Evon, Jamin, Yann, Martins Da Costa, Barbara, Barker, Karen, Shrestha, Sumana, Hutchinson, J Ciaran, Dhariwal, Simran, Goodman, Angharad, Del Nery, Elaine, Gestraud, Pierre, Bhalshankar, Jaydutt, Iddir, Yasmine, Saberi-Ansari, Elnaz, Saint-Charles, Alexandra, Geoerger, Birgit, Marques Da Costa, Maria Eugénia, Pierre-Eugène, Cécile, Janoueix-Lerosey, Isabelle, Decaudin, Didier, Nemati, Fariba, Carcaboso, Angel M, Surdez, Didier, Delattre, Olivier, George, Sally L, Chesler, Louis, Tweddle, Deborah A, Schleiermacher, Gudrun
Format: Article
Language:English
Subjects:
Aminopyridines - therapeutic use
Anaplastic Lymphoma Kinase - genetics
Animals
Humans
Lactams, Macrocyclic - pharmacology
Lactams, Macrocyclic - therapeutic use
Lung Neoplasms - drug therapy
Mice
Neuroblastoma - drug therapy
Neuroblastoma - genetics
Neuroblastoma - metabolism
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Translational Cancer Mechanisms and Therapy
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Summary: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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-22-2274