Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

Abstract

In cancer cells, the nuclear-cytoplasmic transport machinery is frequently disrupted, resulting in mislocalization and loss of function for many key regulatory proteins. In this review, the mechanisms by which tumor cells co-opt the nuclear transport machinery to facilitate carcinogenesis, cell survival, drug resistance, and tumor progression will be elucidated, with a particular focus on the role of the nuclear-cytoplasmic export protein. The recent development of a new generation of selective inhibitors of nuclear export (XPO1 antagonists) and how these novel anticancer drugs may bring us closer to the implementation of this therapeutic strategy in the clinic will be discussed. Signifi cance:The nuclear transport mechanism is dysregulated in many malignancies and is associated with dysfunction of many regulatory proteins. Targeting this mechanism as an anticancer strategy has been compelling, and novel agents that selectively inhibit the nuclear export pathway have demonstrated preliminary evidence of clinical effi cacy with an acceptable safety profi le. Cancer Discov; 4(5); 527-37.

Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

“…5 Exportin 1 (XPO1), also called chromosome region maintenance protein 1 (CRM1), is a critical mediator of nuclear export responsible for shuttling more than 200 known cargo proteins from the nucleus to the cytoplasm, including TSPs and anti-inflammatory and growthregulating proteins. 6,7 XPO1 overexpression has been reported in several hematologic and solid malignancies and is correlated with poor patient outcomes. [7][8][9][10][11][12] XPO1 overexpression is one mechanism by which neoplastic cells inactivate TSPs through nuclear exclusion and thereby circumvent cell-cycle regulation, genome survey, and apoptosis.…”

“…6,7 XPO1 overexpression has been reported in several hematologic and solid malignancies and is correlated with poor patient outcomes. [7][8][9][10][11][12] XPO1 overexpression is one mechanism by which neoplastic cells inactivate TSPs through nuclear exclusion and thereby circumvent cell-cycle regulation, genome survey, and apoptosis. 9 Selinexor is a novel, orally bioavailable small molecule, which inhibits XPO1 by covalently and reversibly binding cysteine-528, an essential residue for XPO1 cargo binding.…”

“…6 Inhibition of XPO1 results in nuclear accumulation of p53, pRb, p21, p27, BRCA1/2, FOXOs, survivin, and other proteins. 6,7 Accumulation of TSPs in the nucleus restores cell-cycle checkpoints and induces growth arrest and apoptosis in malignant cells. 13,14 Preclinical studies in a wide range of sarcoma cell lines and xenografts have demonstrated robust antitumor activity.…”

Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors

“…However, many TSPs such as p53 and p27 execute their tumor suppressor functions mainly in the nucleus and are in part regulated by nuclearcytoplasmic shuttling for a rapid on/off switch. Dysregulation of nuclear-cytoplasmic shuttling affects nuclear activity of various TSPs and can contribute to abnormal cell survival, tumor progression, and drug resistance (3,4). Although many molecules are involved in the shuttling process, alteration of exportin 1 (XPO1) plays a prominent role in tumor pathogenesis.…”

“…Although many molecules are involved in the shuttling process, alteration of exportin 1 (XPO1) plays a prominent role in tumor pathogenesis. XPO1, also known as chromosome region maintenance 1 (CRM1), mediates nuclear export of $200 leucine-rich-nuclear export signal (LR-NES)-containing proteins (4). Importantly, XPO1 is the sole nuclear export receptor for a large number of TSPs involved in apoptotic signaling and cell-cycle regulation.…”