Multiple clinical trials are underway to evaluate the antitumor activity of a new class of protein products that target the cell surface death receptors (DRs) 4 and 5. These include the recombinant human TNF-related apoptosis inducing ligand (TRAIL) and agonistic antibodies specific to DR4 or DR5. The early-phase clinical data is encouraging in suggesting a tolerated safety profile for these products. However, there is a major concern about the occurrence of drug resistance that has been seen in a large number of human cancer cell lines and primary tumors. There are unmet needs in the development of DR-targeted therapies, in terms of both the ability to predict a tumor response and the selection of combinational drugs for overcoming the resistance towards a better clinical efficacy.

Our laboratory investigates cell death and cell survival mechanisms involved in cancer drug action and resistance. Over the past eight years, we have made significant findings on the molecular determinants of TRAIL resistance. We have shown that deficiency of DR4 and/or DR5 on surface membrane is a critical mechanism of cancer cell resistance to the targeted therapies. In some cancer cells, the two receptors are found to be not properly expressed on surface membrane and, instead, are mislocalized in intracellular compartments. We provide evidence for novel mechanisms of DR surface deficiency, which involve deregulation of endocytosis and autophagy pathways in the TRAIL-resistant cells. These data could help identify biomarkers for predication of a tumor response and novel molecular targets for combination drugs to overcome or bypass the resistance mechanisms. This presentation will give an update of the relevant clinical trails and our research findings on DR-targeted therapies.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B246.

Citation Format: Baolin Zhang, Junjie Chen, Xu Di, Yaqin Zhang. Overcoming cancer resistance to death receptor targeted therapies. [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 B246.