Endocytosis of ALK promotes glucose uptake in ALK-amplified neuroblastoma

Abstract

Activated receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), trigger intracellular signaling while undergoing receptor endocytosis. We recently identified a noncanonical mechanism in which RTK-containing endocytic vesicles deliver extracellular glucose to hexokinases associated with the outer mitochondrial membrane, thereby promoting cellular glucose uptake. Whether this mechanism contributes to cancer metabolism, however, remains unknown. Here, using neuroblastoma cell lines with distinct ALK alterations, we investigated the role of ALK endocytosis in glucose uptake. ALK-amplified, but not ALK-mutant, neuroblastoma cells exhibited a [~]40- 50% reduction in glucose uptake following inhibition of ALK or receptor endocytosis. This process was independent of the ERK MAPK and PI3K-AKT pathways but required dynamin-dependent endocytosis, cytoplasmic dynein, and GLUT1. Overexpressed ALK constitutively co-endocytosed with GLUT1 into vesicles transported to mitochondria. Inhibition of ALK activity or endocytosis suppressed glucose uptake without producing an additive effect, indicating that both function within the same pathway. Furthermore, disruption of the endocytic machinery selectively impaired the growth of ALK-amplified neuroblastoma cells. These findings identify ALK endocytosis as a major regulator of glucose uptake in ALK-amplified neuroblastoma and suggest that RTK endocytosis represents a previously unrecognized metabolic vulnerability that may be therapeutically exploitable in RTK-driven cancers.