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Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models

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.

Publication metadata

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


DOI: 10.1158/1078-0432.CCR-22-2274

PubMed id: 36602782


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Funder referenceFunder name
116064 ITCC-P4
PHRC IC2007-09