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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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. / Najem, Safiullah; Langemann, Dörte; Appl, Birgit; Trochimiuk, Magdalena; Hundsdoerfer, Patrick; Reinshagen, Konrad; Eschenburg, Georg.
In: ONCOTARGET, Vol. 7, No. 45, 08.11.2016, p. 72634-72653.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - 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
AU - Najem, Safiullah
AU - Langemann, Dörte
AU - Appl, Birgit
AU - Trochimiuk, Magdalena
AU - Hundsdoerfer, Patrick
AU - Reinshagen, Konrad
AU - Eschenburg, Georg
PY - 2016/11/8
Y1 - 2016/11/8
N2 - 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.
AB - 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.
U2 - 10.18632/oncotarget.12055
DO - 10.18632/oncotarget.12055
M3 - SCORING: Journal article
C2 - 27655666
VL - 7
SP - 72634
EP - 72653
JO - ONCOTARGET
JF - ONCOTARGET
SN - 1949-2553
IS - 45
ER -
