Caspase-8 activation by TRAIL monotherapy predicts responses to IAPi and TRAIL combination treatment in breast cancer cell lines

摘要: The discovery of cancer cell-selective tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-induced generated broad excitement and development TRAIL receptor agonists (TRA) as potential therapy. Studies demonstrating the synergistic combination effect SMAC mimetics TRA further suggested potentially effective treatment in multiple settings. However, predictive biomarkers allowing identification patients that could respond to are lacking. Here, we described a high throughput screen conducted across panel 31 breast cell lines which observed highly activity between inhibitors proteins (IAP) inhibitor (IAPi) AZD5582 ~30% lines. We detected no difference expression levels IAPi or TRAIL-targeted common modulators apoptotic pathway sensitive resistant Synergistic correlated with sensitivity TRAIL, but not single agent. led significantly greater Caspase-8 than (P=0.002). majority (12/14) AZD5582+TRAIL-resistant retained functional death pathway, they were AZD5582+TNFα treatment. This failure complex transduce signal underlies AZD5582+TRAIL resistance. developed 3D spheroid assay demonstrated its suitability for ex vivo analysis biomarker. Altogether, our study link functionality IAPi+TRA It also provided rationale biomarker allow better prediction response IAPi+TRA-based therapies protein biomarkers.