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
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Safiullah Najem1, Doerte Langemann1, Birgit Appl1, Magdalena Trochimiuk1, Patrick Hundsdoerfer2, Konrad Reinshagen1 and Georg Eschenburg1
1 Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2 Department of Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany
Georg Eschenburg, email:
Keywords: neuroblastoma, LCL161, Smac mimetics, chemotherapy, anaplastic lymphoma kinase
Received: January 06, 2016 Accepted: August 27, 2016 Published: September 15, 2016
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.
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