Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in human mutant neuroblastoma cell lines and xenograft models.

Elife 2017 04 20;6. Epub 2017 Apr 20.

Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.

The efficacy of ALK inhibitors in patients with -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 wild-type neuroblastoma cells harboring 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 wild-type neuroblastoma with aberrations.

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http://dx.doi.org/10.7554/eLife.17137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435462PMC
April 2017
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