XPO1 inhibition enhances radiation response in preclinical models of rectal cancer
Menée sur des lignées cellulaires de cancer colorectal et à l'aide de xénogreffes, cette étude montre qu'un inhibiteur de XPO1 peut augmenter la réponse des cellules tumorales aux rayonnements ionisants
Purpose: Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5FU-based chemoradiation prior to surgical resection; however pathological complete response varies from 15 - 20%, prompting the need to identify new radiosensitizers. XPO1 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. Experimental Design: 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. Results: Combination treatment of radiation therapy 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 decreased total survivin levels, resulting in enhanced radiation antitumoral effects. Conclusions: 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.