Protein kinases: emerging therapeutic targets in chronic lymphocytic leukemia

Abstract

Introduction: Although protein kinases are primary targets for inhibition in hematological malignancies, until recently their contribution to chronic lymphocytic leukemia (CLL) was poorly understood. Insights into B-cell receptor signaling and its role in regulating key cellular functions have shed light on candidate protein kinases that are aberrantly activated in CLL. In this regard, protein kinases are now considered as potential drug targets in CLL.

Area covered: This review has covered signaling pathways and associated protein kinases in CLL and the kinase inhibitors currently available in preclinical and clinical investigations. Individual protein kinases that are abnormally active in CLL and the functional consequences of their inhibition are discussed.

Expert opinion: A growing body of evidence suggests that protein kinases are druggable targets for patients with CLL. The emergence of novel and bio-available kinase inhibitors and their promising clinical activity in CLL underscore the oncogenic role of kinases in leukemogenesis. Further investigations directed towards their role as single agents or in combinations may provide insight into understanding the substantial role of kinase-mediated signal transduction pathways and their inhibition in B- CLL.

Figure 1

BCR stimulation by antigen leads to phosphorylation of the immunoreceptor tyrosine-based activation motifs (ITAMs) located in the cytoplasmic tails of CD79a/CD79b by a Src-related PTK, Lyn. Following ITAM phosphorylation, Syk is subsequently recruited and activated by tyrosine phosphorylation, which in turn propagates signal via BLNK, a linker protein to activate Bruton's tyrosine kinase (BTK). Syk and BTK subsequently phosphorylate phosphatidylinositol 3-kinase (PI3K) and phospholipaseCγ2 (PLCγ2), respectively. PI3K, a lipid kinase, phosphorylates phosphatidylinositol-3,4,5-triphosphate, which then recruits other BCR-signaling molecules to the membrane and transmits signal to ser/thr kinase AKT. Activated AKT targets numerous substrates that are functionally pro-apoptotic. In parallel, activated PLCγ2, a phospholipase enzyme, cleaves the membrane phospholipid, phosphatidylinositol-4,5-bisphosphate into diacylglycerol (DAG) and inositol triphosphate, which consequently mobilize calcium and activate protein kinase C (PKC). These events open up a signaling cascade promoting activation of multiple kinases and transcription factors and concurrent protein synthesis. In addition, stromal cells also contribute to the high levels of anti-apoptotic proteins.