Session Speaker
Predicting Tumor Resistance to the Death Receptor-targeted Therapies
Yaqin Zhang, Tatsushi Yoshida, Leslie Rosado Rivera, and Baolin Zhang


The cell surface death receptors are promising targets for cancer therapy. Recombinant human TNF-related apoptosis inducing ligand (TRAIL) and its agnostic antibodies are in clinical trials for treating various malignancies. However, their therapeutic potential is limited by occurring resistance in tumor cells. Non-responsive patients will not benefit from the treatment but may still suffer from the side effects. Our goal has been to identify biomarker(s) for predicating tumor sensitivity to the death receptor targeted therapies.

In this study, we investigated the TRAIL-resistance in human breast cancer cells. We found that TRAIL resistance is associated with constitutive endocytosis of its death receptors (DRs) 4 and 5. Despite their total mRNA and protein expression, TRAIL death receptors, with a higher frequency in DR4, are absent on cell surface in some cell lines. Loss of cell-surface expression of DR4 or DR5 accounts for resistance to their corresponding antibody, and importantly, correlates with a decreased sensitivity to TRAIL. TRAIL-resistance occurs when both receptors are absent on cell surface, regardless of alterations in Bcl-2 family proteins or caspases. Furthermore, inhibition of endocytosis by pharmacological inhibitors or disruption of clathrin-dependent endocytosis signaling components (AP2 and clathrin) restores cell surface expression of the death receptors and sensitize TRAIL-resistant cells to TRAIL-induced apoptosis. Additionally, TRAIL induces internalization of DR4 and DR5 in TRAIL-sensitive cells, thereby delaying or halting TRAIL-induced apoptosis. The results show that loss of cell surface expression of DR4 and DR5 could be evaluated as a biomarker for TRAIL-resistance in human tumors. The results also suggest that the clathrin-mediated endocytosis pathway could be a potential target for therapeutics to overcome tumor resistance to TRAIL receptor-targeted therapies.