Smac mimetic LCL161 supports neuroblastoma chemotherapy in a drug class-dependent manner and synergistically interacts with ALK inhibitor TAE684 in cells with ALK mutation F1174L.

Safiullah Najem,Doerte Langemann,Magdalena Trochimiuk,Konrad Reinshagen,Patrick Hundsdoerfer,Birgit Appl,Georg Eschenburg

doi:10.18632/oncotarget.12055

Abstract

Neuroblastoma is the most common extracranial solid tumor during infancy and childhood.Outcome of high-risk and late-stage disease remains poor despite intensive treatment regimens.Suppressing inhibitor of apoptosis proteins (IAPs) using Smac mimetics (SM) significantly sensitizes neuroblastoma (NB) cells for chemotherapy, however strongly dependent on the cytotoxic drug combined with SM.Therefore, a systematic analysis of the impact of SM in combination with different classes of chemotherapeutics was of crucial importance. Treatment of NB cell lines with SM LCL161 and vinca alkaloids revealed a strong synergistic inhibition of proliferation and significant induction of apoptosis in virtually all established and de novo NB cell lines (n=8).In contrast, combination of anthracyclines or topoisomerase inhibitors with LCL161 showed a synergism for single drugs and/or cell lines only.Furthermore, we could show that insensibility to LCL161-mediated sensitization for chemotherapeutics is associated with aberrant activation of anaplastic lymphoma kinase (ALK) by common mutation F1174L. Inhibition of ALK using TAE684 is able to overcome this resistance in a synergistic fashion, a finding that could be highly relevant for improvement of neuroblastoma therapy.

Highlights

Neuroblastoma is a malignant disease of the sympathetic nervous system and the most prevalent solid extracranial tumor during infancy and childhood
Second mitochondria-derived activator of caspase (Smac) mimetic LBW242 displayed a synergistic gain of chemotherapy on neuroblastoma cell lines in a drug-dependent manner [7]
We determined the abundance of cIAP-1 and X-linked IAP (XIAP) protein in neuroblastoma cell lines (n = 6) using Western blot analysis (Figure 1A)

Summary

Introduction

Neuroblastoma is a malignant disease of the sympathetic nervous system and the most prevalent solid extracranial tumor during infancy and childhood. Prognosis for non-high risk disease is good with 5-year survival > 90%, at the same time more than 50% of patients suffer from metastatic disease at time of diagnosis [1, 2]. Outcome for these patients is still poor in spite of significant therapy improvements in the last years including differentiation therapy or immunotherapy [3]. Deregulated apoptotic machinery is one of the hallmarks of cancer contributing to development and expansion of diverse malignancies [6]

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