A systems biology approach to overcome TRAIL resistance in cancer treatment

Abstract

Over the last decade, our research team has investigated the dynamic responses and global properties of living cells using systems biology approaches. More specifically, we have developed computational models and statistical techniques to interpret instructive cell signaling and high-throughput transcriptome-wide behaviors of immune, cancer, and embryonic development cells. Here, I will focus on our recent works in overcoming cancer resistance. TRAIL (tumor necrosis factor related apoptosis-inducing ligand), a proinflammatory cytokine, has shown promising success in controlling cancer threat due to its ability to induce apoptosis in cancers specifically, while having limited effect on normal cells. Nevertheless, several malignant cancer types, such as fibrosarcoma (HT1080) or colorectal adenocarcinoma (HT29), remain non-sensitive to TRAIL. To sensitize HT1080 to TRAIL treatment, we first developed a dynamic computational model based on perturbation-response approach, to predict a crucial co-target to enhance cell death. The model simulations suggested that PKC inhibition together with TRAIL induce 95% cell death. Subsequently, we confirmed this result experimentally utilizing the PKC inhibitor, bisindolylmaleimide (BIM) I, and PKC siRNAs in HT1080.