Exportin 1 as a Therapeutic Target to Overcome Drug Resistance in Lung Cancer
Maria Vittoria Di Marco1, Alessandro Gasparetto1,2, Roberto Chiarle1,2,3
1Department of Molecular Biotechnology and Health Sciences, University of Turin, 10124 Turin, Italy.
Abstract:
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality, with therapeutic resistance continuing to limit long-term responses. Among emerging resistance mechanisms, dysregulation of nucleocytoplasmic transport has gained attention for its ability to inactivate tumor suppressor pathways. Exportin 1 (XPO1), the primary nuclear export protein, is frequently overexpressed in NSCLC and promotes the cytoplasmic mislocalization of proteins involved in cell cycle control, apoptosis, and DNA repair. This includes key regulators such as p53, FOXO, and RB, whose inactivation supports tumor progression and therapy resistance. Inhibition of XPO1 with selective inhibitors of nuclear export (SINE) compounds, including selinexor, has demonstrated the ability to restore nuclear localization and function of these proteins, thereby enhancing cellular sensitivity to DNA-damaging agents, kinase inhibitors, and immunotherapies. In preclinical NSCLC models, XPO1 inhibition has shown efficacy both as monotherapy and in combination strategies, with particular promise in KRAS- and EGFR-driven tumors. This review explores the role of XPO1 in NSCLC biology and therapy resistance, the rationale for targeting nuclear export, and the current landscape of XPO1-directed clinical development in lung cancer.
Insights
Exportin 1 (XPO1) overexpression drives non-small cell lung cancer (NSCLC) therapy resistance by mislocalizing tumor suppressors. Inhibiting XPO1 restores protein function, enhancing cancer treatment sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality, often complicated by therapeutic resistance.
- Dysregulated nucleocytoplasmic transport, particularly Exportin 1 (XPO1) overexpression, contributes to NSCLC progression and treatment failure.
- XPO1 promotes the export of tumor suppressors like p53, FOXO, and RB, inactivating critical cell cycle and apoptosis pathways.
Purpose of the Study:
- To review the role of XPO1 in NSCLC biology and therapy resistance.
- To explore the rationale for targeting nuclear export in NSCLC treatment.
- To summarize the clinical development of XPO1-directed therapies for lung cancer.
Main Methods:
- Literature review of studies investigating XPO1 function in NSCLC.
- Analysis of preclinical data on XPO1 inhibition in NSCLC models.
- Examination of clinical trial data for selective inhibitors of nuclear export (SINE) compounds.
Main Results:
- XPO1 is overexpressed in NSCLC, correlating with poor prognosis and resistance.
- Selective inhibitors of nuclear export (SINE) compounds restore tumor suppressor function by blocking XPO1.
- XPO1 inhibition shows efficacy in preclinical models, including KRAS- and EGFR-driven NSCLC, as monotherapy and in combination.
Conclusions:
- Targeting XPO1 offers a promising strategy to overcome therapeutic resistance in NSCLC.
- Restoring nuclear localization of tumor suppressors via XPO1 inhibition can re-sensitize tumors to various cancer treatments.
- XPO1-directed therapies are under active clinical investigation for NSCLC patients.
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