Mechanisms of Resistance to the TRK-ALK-ROS1 Inhibitor Entrectinib in Neuroblastoma

Backgroud

Neuroblastoma (NB) is the most common and deadly solid tumor in children and it is characterized by clinical heterogeneity, from spontaneous regression to relentless progression. Evidence from our laboratory and others suggests that the NTRK family of neurotrophin receptors plays critical roles in NB pathogenesis and clinical behavior. NTRK1 (TrkA) is expressed in favorable neuroblastomas and likely contributes to spontaneous regression or differentiation. Conversely, coexpression of NTRK2 (TrkB) and its ligand, brain-derived neurotrophic factor (BDNF) in unfavorable NBs creates an autocrine survival pathway that leads to aggressive behavior, including invasion, metastasis, angiogenesis and drug resistance. We have evidence that targeting the TrkB/BDNF pathway with TRK inhibitors (TRKIs) will effectively kill TrkB-expressing NB cells. We are studying the TRK-ALK-ROS1 inhibitor Entrectinib, which is one of the most potent and effective TRK inhibitors available and is just entering clinical trials at CHOP.

Project Goal

We want to determine the most common mechanisms of Entrectinib resistance, so clinical resistance can either be treated or prevented. We already have five resistant clones that demonstrate at least 3 different mechanisms of resistance. The project will focus on at least one clone and demonstrate the precise mechanism of resistance. I will determine if that resistance can be overcome by inhibiting the bypass mechanism responsible for resistance. These studies will lead directly to more effective and less toxic therapy for children with high-risk NBs.