Background: Neuroblastoma (NB) is characterized by clinical heterogeneity, and the Trk neurotrophin receptors play important roles in this behavior. High-risk NBs frequently overexpress TrkB and its ligand, leading to invasion, metastasis, angiogenesis and drug resistance. We wanted to determine if entrectinib (RXDX-101, Ignyta, Inc.), an orally bioavailable pan-Trk, Alk and Ros1 inhibitor, was effective in our TrkB-expressing NB model.
Methods: We tested the in vitro effects on growth of entrectinib either alone or in combination with the chemotherapeutic agents Irinotecan and Temozolomide (Irino-TMZ) on an SH-SY5Y NB cell line stably transfected with TrkB. These inhibition results were confirmed by both RT-CES and SRB assays. We also studied the in vivo growth inhibition of entrectinib in NB xenografts as a single agent or in combination with Irino-TMZ.
Results: Entrectinib significantly inhibited the growth of TrkB-expressing NB cells in vitro, and it significantly enhanced the growth inhibition of Irino-TMZ when used in combination. Single agent therapy resulted in significant tumor growth inhibition in animals treated with entrectinib alone compared to untreated control animals [p<0.0001 for event-free survival (EFS)]. The addition of entrectinib to Irino-TMZ also significantly improved the EFS of animals compared to vehicle or Irino-TMZ treated animals (p<0.0001 for combination vs. control, p=0.0012 for combination vs. Irino-TMZ). There was no apparent toxicity of entrectinib treatment alone, and no additional toxicity when entrectinib was added to Irino-TMZ.
Conclusions: Our data show that entrectinib significantly inhibits growth of TrkB expressing NB cells both in vitro and in vivo. It also significantly enhances the efficacy of conventional chemotherapy in vitro and in our NB xenograft model. Thus, Entrectinib is a very promising targeted therapy for NBs and other Trk-expressing tumors. Entrectinib is currently entering an industry-sponsored, multi-institutional phase I clinical trial for children and adolescents with NBs and other recurrent or refractory solid tumors.