Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

Breast cancer is the second-leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and whether addition of small molecule inhibitors enhances reovirus-induced cytotoxicity of breast cancer cells. Here, we generate reassortant reoviruses by forward genetics that infect and kill triple-negative breast cancer cells more efficiently than parental viruses. From a high-throughput screen of small molecule inhibitors, we identified topoisomerase inhibitors as drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of cells with topoisomerase inhibitors activates the DNA damage response and infection with reovirus induces robust production of Type III, but not Type I, interferon. Together, data presented show that reassortant viruses generated by forward genetics in combination with topoisomerase inhibitors more efficiently infect and kill triple-negative breast cancer cells.