Mentor Name: Yael Mosse

ALK is a critical oncogenic driver in neuroblastoma, with activating mutations well-established in familial and sporadic cases. Current ALK-targeted kinase inhibitors effectively treat patients with these genetic alterations. However, we have identified a substantial population of neuroblastoma tumors expressing wild-type (WT) ALK that remain dependent on ALK for survival yet are resistant to kinase inhibition. This reveals a critical therapeutic gap: WT ALK exerts essential kinase-independent functions required for neuroblastoma cell viability. Preliminary data from our lab have identified WT ALK-interacting proteins involved in protein translation and ribosomal biogenesis, suggesting ALK mediates scaffolding functions critical for proteostasis. Targeting WT ALK through protein degradation represents a transformative therapeutic strategy for this patient population. Using WT ALK-dependent neuroblastoma models, we will employ CRISPRi-mediated knockdown and kinase-dead ALK overexpression to confirm ALK’s essential role is kinase-independent. We will perform co-immunoprecipitation and proximity labeling to characterize the WT ALK interactome and identify critical protein-protein interactions, validated through cell viability and apoptosis assays. This research will establish ALK degradation as a viable therapeutic strategy for WT ALK-expressing neuroblastoma and inform clinical development of novel ALK-directed therapies.