XPO1: From basic research to clinical treatment (Review)
TL;DR
The present review focuses on the clinical translation of SINE drugs, especially selinexor (KPT-330), in hematologic and solid tumors, critically assesses the limitations of monotherapy and explores the mechanistic basis for synergistic combination strategies.
Abstract
Exportin 1 (XPO1) is a key nuclear export receptor that mediates the nuclear export of tumor suppressor proteins and growth-regulatory mRNAs from the nucleus to the cytoplasm. In several types of cancer, XPO1 is overexpressed or hyperactivated, leading to aberrant cytoplasmic sequestration of key tumor suppressors such as p53, p21, p73, FOXO and Rb. This mislocalization abrogates their nuclear transcriptional functions, disrupting cell cycle arrest, apoptosis and DNA repair, thereby promoting uncontrolled proliferation, survival and therapy resistance. Targeting XPO1 with selective inhibitors of nuclear export (SINE) has emerged as a promising anticancer strategy. The present review systematically examines the molecular mechanisms of XPO1-driven tumorigenesis and its rationale as a therapeutic target. The present review focuses on the clinical translation of SINE drugs, especially selinexor (KPT-330), in hematologic and solid tumors, critically assesses the limitations of monotherapy and explores the mechanistic basis for synergistic combination strategies. Ongoing clinical trials and future directions to optimize therapeutic efficacy are also highlighted. Collectively, the present review aims to provide a comprehensive foundation for advancing basic and clinical research on XPO1-targeted therapies.