Chronic Lymphocytic Leukemia: Exploiting Vulnerabilities with Targeted Agents.

The field of oncology has been transformed over the course of the last 20 years in large part due to the enhanced understanding of cellular biology and cellular signaling. The indolent natural history of chronic lymphocytic leukemia (CLL) has permitted extensive study of cancer biology and can in some ways be thought of a model for understanding and translating concepts to other diseases. By systematically probing the biology of CLL cells and working out in stepwise fashion the transduction of signals from the surface immunoglobulin to nuclear transcription factors, investigators have paved the way for rational targeting of therapies at natural vulnerabilities that mimic oncogene addiction. These key targets include Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), Src, Bcl2, and cyclin-dependent kinases (CDKs). In this review, we will consider these proteins and describe the current and future molecules designed to target them in CLL.