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ORAL 40 - Biology 1 (ID 154)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
ORAL40.07 - Xpo1 Inhibition: A Promising Therapeutic Strategy in Thymic Epithelial Tumors (ID 1230)
16:45 - 18:15 | Author(s): F. Conforti
Growing evidence suggests that nuclear–cytoplasmic transport is frequently dysregulated in cancer cells, and is involved in promoting carcinogenesis, cell survival, drug resistance and tumor progression. In particular, enhanced nuclear export is one mechanism by which malignant cells inactivate tumor suppressor proteins (TSPs). Inhibition of XPO1 (CRM1), the main karyopherin involved in the nuclear export of TSPs, restores nuclear localization and function of TSPs in several preclinical models. Selinexor(KPT-330) is an XPO1 inhibitor being tested clinically in solid tumors and hematological malignancies that showed some activity in patients with thymic epithelial tumors (TETs). Here, we describe the activity of selinexor in preclinical models of TETs.
Thymoma (IU-Tab1, T1682), thymic carcinoma (Ty82, T1889, MP57) and immortalized normal thymic epithelial cells (TEC84) treated with selinexor or vehicle were assayed by CellTiter-Glo and flow cytometry. Western blot analysis of nuclear and cytoplasmic protein fractions and immunofluorescence assays were used to study the cellular sublocalization of XPO1 cargoes before and after treatment. The effect of selinexor on cell migration was determined using a wound-healing assay. A selixinor-resistant cell line was generated by growing selinexor-sensitive IU-Tab1 cells at increasing concentrations of the drug. Mutational status and copy number of the XPO1 gene was assessed by Q- PCR and Sanger sequencing.
All TET cell lines were sensitive to selinexor (IC~50~ 90-250 nM) with the exception of T1682 (thymoma type B), which showed intrinsic drug resistance (IC~50~ > 1000 nM). In the sensitive cell lines, selinexor treatment induced G1 (MP57) or G2 (IU-Tab1, Ty82) cell-cycle arrest at 24 hours, and induced apoptosis 2-5 fold over untreated cells by 72 hours. The cytotoxic effects of selinexor were not observed in immortalized normal TEC84 cells at nanomolar concentrations, and required higher concentrations (IC~50 ~800nM) to induce a cytostatic effect. Drug treatment led to increased nuclear concentrations of several TSPs involved in cell cycle regulation (e.g. p21, p27), genomic stability (p53) and induction of apoptosis (FOXO3a) and also reduced the total cellular expression of the oncogenic protein NF-kB. These results were confirmed with siRNA knockdown of XPO1. In addition,selinexor treatment impaired tumor cell migration and had cytotoxic synergistic effect in combination with doxorubicin or etoposide in T1889 and IU-Tab1 cell lines, increasing nuclear accumulation of the XPO1 cargo protein, Topoisomerase IIα. Furthermore, we demonstrated that selinexor-resistant cell line has similar growth rates to their parental cells, however overexpress XPO1 due to gene amplification, confirming the importance of aberrant XPO1 activity in TET survival.
Our data show the importance of XPO1 in TETs biology and demonstrate activity of selinexor in preclinical models, further supporting the planned Phase II trial in patients with TETs.
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