Abstract B22: BAY61-3606 sensitizes colon cancer cells to TRAIL-induced apoptosis by targeting TRAIL-R1 and RIPK1.

Abstract

Abstract Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) appears to be a promising candidate for cancer therapeutics because of its ability to preferentially induce apoptosis in malignant cells. However, heterogeneous sensitivity of cancer cells to TRAIL-induced apoptosis may lead to persistent growth of TRAIL-resistant cells, and preclude successful treatment of cancer by TRAIL. Here we show that that the orally available tyrosine kinase inhibitor BAY61-3606 potently enhances sensitivity of human colon cancer cells to TRAIL-induced apoptosis, and that this is associated with upregulation of TRAIL-R1 and downregulation of the receptor-interacting serine/threonine-protein kinase 1 (RIPK1). Although treatment with BAY61-3606 only caused moderate colon cancer cell death, it significantly enhanced TRAIL-induced killing. This could be efficiently blocked by the general caspase inhibitor z-VAD-fmk, indicating TRAIL primarily induced apoptosis in the presence of BAY61-3606. Interestingly, exposure of colon cancer cells resulted in upregulation of TRAIL-R1 and downregulation of RIPK1, suggesting that they may play an important role in BAY61-3606-mediated sensitization of colon cancer cells to TRAIL-induced apoptosis. Taken together, our results suggest that combination with BAY61-3606 may be a useful strategy to improve the therapeutic efficacy of TRAIL in the treatment of colon cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B22. Citation Format: Jipei Du, Yan Li, Xinyuan Wang, Rao Cheng, Degao Chen, Ji Zhang, Yufang Wang. BAY61-3606 sensitizes colon cancer cells to TRAIL-induced apoptosis by targeting TRAIL-R1 and RIPK1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B22.