(EAY 131-F MATCH): Crizotinib in Patients with Tumors (Other Than Adenocarcinoma of Lung or ALCL) with ALK Translocations
Genomic alterations involving the anaplastic lymphoma kinase (ALK) gene are known oncogenic drivers of a variety of malignancies [1-4]. In the wild-type state, activation of the ALK protein is thought to be potentially mediated by ligand-induced dimerization; however, the role that ALK plays in normal physiology remains poorly understood. Oncogenic activation of ALK can occur via a variety of mechanisms including mutation (e.g. in neuroblastomas) and recurrent gene rearrangements. In the rearranged state, the intact tyrosine kinase domain of ALK is fused to a variety of upstream partners, with the breakpoint of ALK being highly conserved across different fusions. These 5¿ partners contribute leucine zipper or coiled-coil domains that result in ligand-independent activation and constitutive activation of the ALK tyrosine kinase. This, in turn, results in activation of downstream signaling involving the MAPK, PI3K, and JAK/STAT pathways and increased cell growth and proliferation .
NCG 275215 F