Schematic overview of downstream ALK signaling through MAPK and PI3K/AKT/mTOR signaling pathways. ALK is a classical receptor tyrosine kinase consisting of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain.⁷⁶ In ALK fusions such as KIF5B-ALK, the amino-terminal fusion partner is fused to the intracellular tyrosine kinase domain of ALK, leading to constitutive activation of downstream signaling, including RAS-RAF-MEK-ERK (MAPK) and PI3K/AKT/mTOR signaling pathways. MAPK pathway activation ultimately leads to phosphorylation of downstream ERK, which can enter the nucleus and increase the transcription of various effector genes, including the gene encoding for Cyclin D1 (CCND1). Translation of CCND1 messenger RNA to the Cyclin D1 protein is mTOR-dependent.⁷⁷ Figure adapted from Emile et al,² with permission from the authors.