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

Hui Qin Wang,Nanxin Li,Jens U Wuerthner,Noelito Timple,Yichen Cao,Fang Li,Alan Huang,Juliet A Williams,Xiaoyan Li,Jinsheng Liang,David A Ruddy,William R Sellers,Ensar Halilovic,Sebastien Jeay,Shailaja Kasibhatla,Daniel P Rakiec

doi:10.7554/elife.17137

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.

Highlights

Neuroblastoma is a common pediatric solid tumor that arises from neural crest cells, typically in the adrenal medulla or paraspinal ganglia with metastases to bone and bone marrow in high-risk cases (Maris, 2010)
The identification of activating ALK mutations and the demonstration of the oncogenic role of mutant ALK have established ALK as a therapeutic target in neuroblastoma, clinical studies of crizotinib and ceritinib in pediatric cancers have shown that patients with ALK-mutated neuroblastoma responded less favorably than pediatric patients with ALK-rearranged tumors, such as anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT) (Mosseet al., 2013; Birgit Geoerger et al, 2015)
Previous preclinical work has shown that crizotinib inhibited growth of neuroblastoma xenografts expressing ALK R1275Q or amplified wild-type ALK, but failed to inhibit growth of xenografts harboring F1174L-mutated ALK (Bresler et al, 2011)

Summary

Introduction

Neuroblastoma is a common pediatric solid tumor that arises from neural crest cells, typically in the adrenal medulla or paraspinal ganglia with metastases to bone and bone marrow in high-risk cases (Maris, 2010). It remains a leading cause of childhood cancer-related death despite the use of multimodal dose-intensive chemotherapy, radiation therapy and immunotherapeutic strategies (Smith et al, 2010). Somatic mutations in ALK are found as oncogenic drivers in up to 10% of sporadic neuroblastoma with a gene amplification frequency of approximately 2% (Chen et al, 2008; George et al, 2008; Janoueix-Lerosey et al, 2008; Mosseet al., 2008).

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