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Lookup NU author(s): Dr Lindi Chen, Professor Deborah Tweddle
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
©2023 The Authors; Published by the American Association for Cancer Research.PURPOSE: 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. EXPERIMENTAL DESIGN: 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). RESULTS: 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. CONCLUSIONS: 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.
Author(s): Tucker ER, Jimenez I, Chen L, Bellini A, Gorrini C, Calton E, Gao Q, Che H, Poon E, Jamin Y, Martins Da Costa B, Barker K, Shrestha S, Hutchinson JC, Dhariwal S, Goodman A, Del Nery E, Gestraud P, Bhalshankar J, Iddir Y, Saberi-Ansari E, Saint-Charles A, Geoerger B, Marques Da Costa ME, Pierre-Eugene C, Janoueix-Lerosey I, Decaudin D, Nemati F, Carcaboso AM, Surdez D, Delattre O, George SL, Chesler L, Tweddle DA, Schleiermacher G
Publication type: Article
Publication status: Published
Journal: Clinical Cancer Research
Year: 2023
Volume: 29
Issue: 7
Pages: 1317-1331
Print publication date: 01/04/2023
Online publication date: 03/04/2023
Acceptance date: 03/01/2023
Date deposited: 17/04/2023
ISSN (print): 1078-0432
ISSN (electronic): 1557-3265
Publisher: American Association for Cancer Research
URL: https://doi.org/10.1158/1078-0432.CCR-22-2274
DOI: 10.1158/1078-0432.CCR-22-2274
PubMed id: 36602782
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