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
Abstract
Neuroblastoma is the most common extracranial solid tumor in infants and children. Despite intensive treatment regimens, outcomes for high-risk and late-stage disease remain poor. Targeting inhibitor of apoptosis proteins (IAPs) with Smac mimetics (SMs) has been shown to significantly enhance the sensitivity of neuroblastoma (NB) cells to chemotherapy, though the effect is highly dependent on the specific cytotoxic agent used in combination with SMs. Therefore, a systematic evaluation of SMs in conjunction with various classes of chemotherapeutics was essential.
Treatment of NB cell lines with the SM LCL161 and vinca alkaloids resulted in strong synergistic inhibition of cell proliferation and marked induction of apoptosis across nearly all tested established and de novo NB cell lines (n=8). In contrast, combining LCL161 with anthracyclines or topoisomerase inhibitors demonstrated synergy in only select drugs or cell lines.
Moreover, we found that resistance to LCL161-mediated chemosensitization is linked to aberrant activation of anaplastic lymphoma kinase (ALK) due to the common F1174L mutation. Importantly, this resistance can be overcome through ALK inhibition using TAE684, leading to a synergistic therapeutic effect—an insight that could significantly improve NVP-TAE684 neuroblastoma treatment strategies.