Abstract
The majority of high-risk neuroblastoma patients are refractory to, or relapse on, current treatment regimens, resulting in 5-year survival rates of less than 50%. This emphasizes the urgent need to identify novel therapeutic targets. Here, we report that high PIM kinase expression is correlated with poor overall survival. Treatment of neuroblastoma cell lines with the pan-PIM inhibitors AZD1208 or PIM-447 suppressed proliferation through inhibition of mTOR signaling. In a panel of neuroblastoma cell lines, we observed a marked binary response to PIM inhibition, suggesting that specific genetic lesions control responses to PIM inhibition. Using a genome-wide CRISPR-Cas9 genetic screen, we identified NF1 loss as the major resistance mechanism to PIM kinase inhibitors. Treatment with AZD1208 impaired the growth of NF1 wild-type xenografts, while NF1 knockout cells were insensitive. Thus, our data indicate that PIM inhibition may be a novel targeted therapy in NF1 wild-type neuroblastoma. Mol Cancer Ther; 17(4); 849-57. ©2018 AACR.
Highlights
Neuroblastoma is a pediatric malignancy originating from precursor cells of the sympathetic nervous system [1]
High expression of either PIM1, -2, or -3 was significantly correlated with poor overall survival in this cohort
Novel therapeutic targets in neuroblastoma should ideally be targetable by drugs that are currently in use or development for more frequent adult malignancies
Summary
Neuroblastoma is a pediatric malignancy originating from precursor cells of the sympathetic nervous system [1]. It accounts for 8% to 10% of all childhood cancers and is the most common type of cancer diagnosed in infants [2]. Tumor behavior is highly heterogeneous, varying from spontaneous regression to aggressive metastatic disease. Patients with high-risk tumors have a poor prognosis due to refractory or relapsed disease, with 5-year survival rates of less than 50% [3]. Compared with more common malignancies, relatively few targeted agents are being evaluated for the treatment of neuroblastoma. It is essential to identify novel targeted therapies for the treatment of neuroblastoma
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