Abstract A42: H-Ras regulates the dynamics of TRAIL death receptors

Multiple clinical trials are ongoing to evaluate the potential antitumor activity of recombinant human TNF-related apoptosis inducing ligand (rhTRAIL) and its agonistic antibodies. These protein therapies act through death receptors (DRs) 4 and/or 5 on the cell surface, followed by activation of a caspase cascade and apoptotic cell death. We have previously shown that DR4 and/or DR5 are mislocalized in nucleus and/or cytoplasm in some cancer cells thereby rendering cellular resistance to the targeted therapies. In this study, we have found a correlation between H-Ras expression and TRAIL resistance in the NCI60 panel of human cancer cell lines. The elevated expression of H-Ras is also generally associated with a deficiency of TRAIL death receptors on cell surface. Blockade of H-Ras activity in TRAIL-resistant cells upregulated the surface expression of both DR4 and DR5 without changing their total protein expressions. Subsequently, the cells were sensitized to apoptosis induction by the targeted therapies. To our knowledge, this is the first evidence that oncogenic H-Ras is involved in the regulation of subcellular localization of TRAIL death receptors. H-Ras, along with other Ras GTPases, is known to stimulate outgrowth of cancer cells. Our data suggest that H-Ras may elicit its oncogenic activity at least partly by blocking cytokine-induced apoptosis of cancer cells. Additional studies are warranted to evaluate the therapeutic potential of combinational therapies to simultaneously target H-Ras and TRAIL receptors. Citation Format: Jun-jie Chen, Xu Di, Yaqin Zhang, William Bozza, Baolin Zhang. H-Ras regulates the dynamics of TRAIL death receptors. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A42. doi: 10.1158/1557-3125.RASONC14-A42