Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in human ALK mutant neuroblastoma cell lines and xenograft models
- Novartis Institutes for BioMedical Research, United States
- Novartis Institutes for BioMedical Research, Switzerland
- Genomics Institute of the Novartis Research Foundation, United States
Abstract
The efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of TP53 wild-type neuroblastoma cells harboring ALK amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells. We further demonstrate that concurrent inhibition of MDM2 and ALK was able to overcome ceritinib resistance conferred by MYCN upregulation in vitro and in vivo. Together, combined inhibition of ALK and MDM2 may provide an effective treatment for TP53 wild-type neuroblastoma with ALK aberrations.
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Author details
Funding
Novartis
- Fang Li
The research was funded by Novartis, Inc., where all authors were employees at the time the study was conducted. The authors declare no other competing financial interests.
Ethics
Animal experimentation: All in vivo studies were reviewed and approved by the Novartis Institutes of Biomedical Research Institutional Animal Care and Use Committee (IACUC) in accordance with applicable local, state, and federal regulations.If needed, a letter from the IACUC Chair can be provided to confirm that all in vivo studies were reviewed and approved by the Novartis IACUC. Below is the contact of the Novartis IACUC Chair.CeCe Brotchie-Fine, MA, CPIAManager, Animal Welfare ComplianceIACUC Chair & Animal Welfare OfficerT +1 617 871 5064M+1 617 834 4784Email: Candice.brotchie-fine@novartis.comNovartis Institutes for BioMedical Research, Inc.700 Main Street, 460 ACambridge, MA 02139 USA
Copyright
© 2017, Wang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in human ALK mutant neuroblastoma cell lines and xenograft models
eLife 6:e17137.
https://doi.org/10.7554/eLife.17137
