Ovarian cancer is the most lethal gynecological
cancer in the US. Standard treatment consists of surgery followed by
chemotherapies relying on apoptotic
tumor cell death. Most women with advanced stage disease will relapse, suggesting that this disease is characterized by primary and acquired resistance to
chemotherapy, and novel approaches to treatment are greatly needed. Low
Caspase 8 expression levels in
ovarian cancers correlate with resistance to apoptotic
chemotherapy, and a subpopulation of patients with low
Caspase 8 levels exhibit poorer overall survival after standard-of-care treatment. We hypothesized that low
Caspase 8 function reduces the ability of
cancer cells to undergo apoptosis when exposed to standard
chemotherapy and that second mitochondria-derived activator of
caspases (Smac)-mimetics could increase cell death in combination with
chemotherapy. Here we show that combination treatment with a Smac-mimetic can target
tumor cells with low
Caspase 8 and induce necroptotic cell death. We investigated the in vitro effect of Smac-mimetic added to
carboplatin and
paclitaxel treatment of
ovarian cancer cells expressing wild type and low
Caspase 8 levels, which resulted in a 2-4-fold enhancement of cell death. Mice bearing subcutaneous or intraperitoneal ovarian xenografts showed greater aggressiveness of
Caspase 8-deficient versus wild-type
tumors; combined in vivo treatment with
chemotherapy and Smac-mimetic resulted in >50% decrease in low
Caspase 8 xenograft growth, as well as significantly enhanced overall survival, especially when given simultaneously with
paclitaxel. Surprisingly, Smac-mimetic on the same day as
carboplatin decreased mouse survival compared to when it was given on a sequential day of treatment. The antagonism was associated with a decrease in DNA damage markers, emphasizing the importance of optimizing timing of drug administration. Clinical validation of such approaches is needed to increase the effectiveness of current standard
ovarian cancer treatment.