Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models.
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Authors
Tucker, ER
Jiménez, 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-Eugène, C
Janoueix-Lerosey, I
Decaudin, D
Nemati, F
Carcaboso, AM
Surdez, D
Delattre, O
George, SL
Chesler, L
Tweddle, DA
Schleiermacher, G
Jiménez, 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-Eugène, C
Janoueix-Lerosey, I
Decaudin, D
Nemati, F
Carcaboso, AM
Surdez, D
Delattre, O
George, SL
Chesler, L
Tweddle, DA
Schleiermacher, G
Document Type
Journal Article
Date
2023-04-03
Date Accepted
2023-01-03
Abstract
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.
Citation
Clinical Cancer Research, 2023, pp. CCR-22-2274 -
Source Title
Clinical Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
1557-3265
1557-3265
Collections
Research Team
Paediatric Tumour Biology
Computational Biology
Computational Biology