Molecular Pathways Inhibition of ALK Signaling for Cancer Therapy

Paradigm shifting advances in cancer can occur after discovering the key oncogenic drivers of the malignant process, understanding their detailed molecular mechanisms, and exploiting this transdisciplinary knowledge therapeutically. A variety of human malignancies have anaplastic lymphoma kinase (ALK) translocations, amplifications, or oncogenic mutations, including anaplastic large cell lymphoma, inflammatory myofibroblastic tumors, non–small cell lung cancer, and neuroblastoma. This finding has focused intense interest in inhibiting ALK signaling as an effective molecular therapy against diseases with ALK-driven pathways. Recent progress in the elucidation of the major canonical signaling pathways postulated to be activated by NPM-ALK signaling has provided insight into which pathways may present a rational therapeutic approach. The identification of the downstream effector pathways controlled by ALK should pave the way for the rational design of ALK-inhibition therapies for the treatment of a subset of human cancers that harbor ALK aberrations. (Clin Cancer Res 2009;15(18):5609–14)