oa Nuclear Transport Drugs For Cancer: Bench To Bedside

Trafficking of biological materials across nuclear membrane is an evolutionarily conserved mechanism that maintains normal eukaryotic cell homeostasis. Eukaryotes shuttle proteins and RNAs in and out of the cell nucleus using highly complex gated machinery. Smaller entities can enter and exit the nuclear pore through diffusion. The movement of most of the proteins and RNAs, however, requires active transport that is mediated by specialized carriers in a strictly controlled manner. Such energy dependent trafficking occurs through the nuclear pore complex (NPC) that is embedded in the nuclear membrane. The last two decades have witnessed tremendous advancements in the understanding of the NPC. Such studies have helped in the characterization of major nuclear transport mediators belonging to the Karyopherin family proteins that maintain proper compartmentalization of micro- and macro-molecules. This is functionally critical for tumor suppressor proteins (TSPs) and transcription factors (TFs) that require nuclear retention and sequence specific DNA alignment to modulate their target gene expression or conduct genome surveillance activity. Indeed, cancer cells have evolved methods to disturb the nuclear traffic by abnormal expression of the nuclear exporters particularly exportin 1 (Xpo1) that leads to a cascade of de-regulations favoring uncontrolled growth and loss of surveillance within the cells. Major cancer hallmarks have been shown to be influenced by Xpo1 de-regulation directly or indirectly. Recently, specific inhibitors of nuclear export (SINE) have been developed as a broad form of therapy targeting global re-alignment of multiple TSPs in the correct cellular compartment through inhibition of Xpo1 to rein in cancer. SINEs are currently undergoing Phase I and Phase Ib/II clinical evaluation. The drugs show single agent efficacy both in solid tumors and hematological malignancies.