CBL Dysregulation in Cancer: Mechanisms of Oncogenic Signaling and Therapeutic Potential

CBL is a multifunctional protein with E3 ubiquitin ligase and adaptor capacities, critical to regulating tyrosine kinase signaling pathways. CBL mutations have been identified and most widely characterized in myeloid malignancies, while alterations in solid tumors have also been found. Given its essential role in signaling regulation, disrupted CBL function contributes to oncogenesis and tumor progression. Here we review the mechanisms of CBL dysregulation in cancer, including an overview of mutations identified in leukemias, the impacts of mutant CBL expression on cellular signaling, and how these signaling alterations have been investigated using targeted inhibitors. In addition, CBL mutations identified in solid tumors are described, as well as the mechanisms underlying dysregulation of wild-type CBL function in several malignancies. A consolidated molecular view of disrupted CBL function in cancer is detailed, concluding with descriptions of preclinical approaches to modulate CBL function and identified tool compounds that target CBL regulation.