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Figure S2 from Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models

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posted on 2023-04-01, 00:20 authored by Elizabeth R. Tucker, Irene Jiménez, Lindi Chen, Angela Bellini, Chiara Gorrini, Elizabeth Calton, Qiong Gao, Harvey Che, Evon Poon, Yann Jamin, Barbara Martins Da Costa, Karen Barker, Sumana Shrestha, J. Ciaran Hutchinson, Simran Dhariwal, Angharad Goodman, Elaine Del Nery, Pierre Gestraud, Jaydutt Bhalshankar, Yasmine Iddir, Elnaz Saberi-Ansari, Alexandra Saint-Charles, Birgit Geoerger, Maria Eugénia Marques Da Costa, Cécile Pierre-Eugène, Isabelle Janoueix-Lerosey, Didier Decaudin, Fariba Nemati, Angel M. Carcaboso, Didier Surdez, Olivier Delattre, Sally L. George, Louis Chesler, Deborah A. Tweddle, Gudrun Schleiermacher

PDTC experimental data

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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.

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