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XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer
Journal article   Open access   Peer reviewed

XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer

Isabel Ferreiro-Neira, Nancy E Torres, Lukas F Liesenfeld, Carlos H F Chan, Tristan Penson, Yosef Landesman, William Senapedis, Sharon Shacham, Theodore S Hong and James C Cusack
Clinical cancer research, Vol.22(7), pp.1663-1673
04/01/2016
DOI: 10.1158/1078-0432.CCR-15-0978
PMID: 26603256
url
https://doi.org/10.1158/1078-0432.CCR-15-0978View
Published (Version of record) Open Access

Abstract

Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5-fluorouracil-based chemoradiation prior to surgical resection; however pathologic complete response varies from 15% to 20%, prompting the need to identify new radiosensitizers. Exportin 1 (XPO1, also known as chromosome region 1, CRM1) mediates the nuclear export of critical proteins required for rectal cancer proliferation and treatment resistance. We hypothesize that inhibition of XPO1 may radiosensitize cancer cells by altering the function of these critical proteins resulting in decreased radiation resistance and enhanced antitumoral effects. To test our hypothesis, we used the selective XPO1 inhibitor, selinexor, to inhibit nuclear export in combination with radiation fractions similar to that given in clinical practice for rectal cancer: hypofractionated short-course radiation dosage of 5 Gy per fraction or the conventional long-course radiation dosage of 1 Gy fractions. Single and combination treatments were tested in colorectal cancer cell lines and xenograft tumor models. Combination treatment of radiotherapy and selinexor resulted in an increase of apoptosis and decrease of proliferation compared with single treatment, which correlated with reduced tumor size. We found that the combination promoted nuclear survivin accumulation and subsequent depletion, resulting in increased apoptosis and enhanced radiation antitumoral effects. Our findings suggest a novel therapeutic option for improving radiation sensitivity in the setting of rectal cancer and provide the scientific rationale to evaluate this combination strategy for clinical trials.
 Hydrazines - pharmacology Apoptosis - drug effects Apoptosis - radiation effects Tumor Burden - radiation effects Humans Radiation-Sensitizing Agents - pharmacology Radiation Combined Modality Therapy Rectal Neoplasms - radiotherapy Dose-Response Relationship, Drug Radiation Tolerance - drug effects Triazoles - pharmacology Xenograft Model Antitumor Assays Animals Tumor Burden - drug effects Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors Cell Line, Tumor Inhibitor of Apoptosis Proteins - metabolism Mice Rectal Neoplasms - metabolism Rectal Neoplasms - pathology Karyopherins - antagonists & inhibitors Disease Models, Animal

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