BCR-ABL Inhibitors as Sensitizing Agents for Cancer Chemotherapy

Abstract

Abstract Loss of cell cycle control causing uncontrolled cell proliferation is the hallmark of cancer. The cyclin-dependent kinases (CDKs), along with cyclins, serve as check points on the process of cell division and growth. Aberrant expression of these kinases results in cell diversion from the path of senescence to proliferation, leading to cancer development. Targeting CDKs thus serves as an effective anticancer strategy. Ever since the development of the first-generation CDK inhibitors such as alvocidib, numerous efforts have been made to develop more potent and selective CDK inhibitors. The first-generation pan inhibitors have relatively broad spectrum of CDK inhibitory activity with diverse off-target effects. The second-generation CDK inhibitors such as palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib are more potent and selective as compared to the first-generation inhibitors. They block the G1- to S-phase transition of the cell cycle. Moreover, CDK inhibitors also inhibit the phosphorylation of the retinoblastoma (Rb) protein, an essential component of G1- to S-phase cell transition. Recently, the United States Food and Drug Administration (USFDA) approved palbociclib and ribociclib for the treatment of hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. Here we discuss some most common and efficacious CDK inhibitors as sensitizing agents for cancer chemotherapy.