In:
eLife, eLife Sciences Publications, Ltd, Vol. 6 ( 2017-04-20)
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.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.17137.001
DOI:
10.7554/eLife.17137.002
DOI:
10.7554/eLife.17137.003
DOI:
10.7554/eLife.17137.004
DOI:
10.7554/eLife.17137.005
DOI:
10.7554/eLife.17137.006
DOI:
10.7554/eLife.17137.007
DOI:
10.7554/eLife.17137.008
DOI:
10.7554/eLife.17137.009
DOI:
10.7554/eLife.17137.010
DOI:
10.7554/eLife.17137.011
DOI:
10.7554/eLife.17137.012
DOI:
10.7554/eLife.17137.013
DOI:
10.7554/eLife.17137.014
DOI:
10.7554/eLife.17137.015
DOI:
10.7554/eLife.17137.016
DOI:
10.7554/eLife.17137.017
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2017
detail.hit.zdb_id:
2687154-3
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