Selinexor Sensitizes TRAIL-R2-Positive TNBC Cells to the Activity of TRAIL-R2xCD3 Bispecific Antibody

• Published in: Cells (Basel, Switzerland) Vol. 9; no. 10; p. 2231
• Main Authors: Martini, Silvia, Figini, Mariangela, Croce, Aurora, Frigerio, Barbara, Pennati, Marzia, Gianni, Alessandro Massimo, De Marco, Cinzia, Daidone, Maria Grazia, Argueta, Christian, Landesman, Yosef, Zaffaroni, Nadia, Satta, Alessandro
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01-10-2020; MDPI
• Subjects: Antibodies; Antigens; Antitumor activity; Apoptosis; Biotechnology; Bispecific antibodies; bispecific antibody; Breast cancer; CD3 antigen; Cell cycle; Cell growth; Cell receptors; Cloning; Dosage and administration; Drug dosages; Drug therapy; Experiments; Growth inhibition; Immune system; Immunotherapy; Lymphocytes; Lymphocytes T; Medical prognosis; Nuclear transport; Physiological aspects; Proteins; Selinexor; survivin; T cell receptors; T cells; TRAIL protein; TRAIL-R2; Triple negative breast cancer; Tumor necrosis factor; Tumors; United States; Italy; United States > US; Switzerland; Germany
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9102231

Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis and limited therapeutic options. Recent advances in the immunotherapy field have enabled the development of new treatment strategies, among which the use of bispecific antibodies (BsAbs), able to redirect T cells against tumors, has shown promising results. In particular, a BsAb that uses TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) as a target was constructed and demonstrated good results in redirecting CD3+ T cells to kill TRAIL-R2-expressing TNBC cells. In the present study, we investigated whether treatment with selinexor, a selective inhibitor of nuclear export (SINE) targeting exportin-1/chromosome maintenance protein 1 (XPO1/CRM1), could potentiate the antitumor activity of this BsAb. In combination experiments, we found that selinexor-exposed TNBC cells exhibited greater growth inhibition when treated with the TRAIL-R2xCD3 BsAb than that expected by simple additivity. Similarly, the apoptosis rate in selinexor/TRAIL-R2xCD3 BsAb-treated TNBC cells was significantly higher than that observed after exposure to either single agent. Together, our results suggest that the combination of selinexor and TRAIL-R2xCD3 BsAb can be a viable anticancer strategy and indicate this treatment as a promising therapeutic option for TNBC patients.