Smac mimetics are being developed as a new class of anticancer therapies. Since the single-agent activity of Smac mimetics is very limited, rational combinations represent a viable strategy for their clinical development. The combination of Smac mimetics with TRAIL may be particularly attractive due to the low toxicity of TRAIL to normal cells and the synergistic antitumor activity observed for the combination. In the present study, we have investigated the combination synergy between TRAIL and a potent Smac mimetic, SM-164 in vitro and in vivo and the underlying molecular mechanism of action for the synergy. Our study demonstrates that SM-164 is highly synergistic with TRAIL in vitro in both TRAIL-sensitive and TRAIL-resistant cancer cell lines of breast, prostate, and colon cancer. Furthermore, the combination of SM-164 with TRAIL induces rapid tumor regression in vivo in a breast cancer xenograft model in which either agent is ineffective. Our data shows that XIAP and cIAP1, but not cIAP2, work in concert to attenuate the activity of TRAIL; SM-164 strongly enhances TRAIL activity by concurrently targeting XIAP and cIAP1. Moreover, while RIP1 plays a minimal role in TRAIL's activity as a single agent, it is required for the synergistic interaction between TRAIL and SM-164. Our present study provides a strong rationale to develop the combination of SM-164 and TRAIL as a new therapeutic strategy for the treatment of human cancer.
- Received September 17, 2010.
- Revision received January 19, 2011.
- Accepted February 12, 2011.
- Copyright © 2011, American Association for Cancer Research.