A TRAIL-R1-specific ligand in combination with doxorubicin selectively targets primary breast tumour cells for apoptosis
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KeywordsBreast Cancer Doxorubicin Chronic Lymphocytic Leukaemia Normal Breast Tissue T47D Cell
Although the majority of tumour cell lines, including breast cancer cell lines, are sensitive to the death-inducing ligand and potential cancer biotherapeutic TNF-related apoptosis-inducing ligand (TRAIL), most primary tumours are TRAIL-resistant. Importantly, doxorubicin, a chemotherapeutic agent commonly used in breast cancer, has previously been shown to sensitize TRAIL-resistant breast cancer cell lines to TRAIL. Furthermore, using receptor-selective ligands (patent filed by MRC Technology) specific for the TRAIL death receptors, TRAIL-R1/TRAIL-R2, we have previously shown that primary leukaemic cells isolated from patients with chronic lymphocytic leukaemia can be selectively sensitized to apoptosis by combining an a histone deacetylase inhibitor (HDACi) with a TRAIL-R1-specific form of TRAIL/TRAIL-R1 mAb.
Methods and results
To examine the potency of TRAIL-R1/TRAIL-R2-specific ligands in breast cancer, a panel of breast tumour cell lines was employed, which included the TRAIL-resistant breast cancer cell line, T47D. In addition, a modified approach of culturing primary breast tumour explants ex vivo to maintain their three-dimensional architecture provided a more clinically relevant breast tumour model. Importantly, all TRAIL-sensitive breast tumour cell lines responded only to a TRAIL-R1-specific form of TRAIL. Despite expressing TRAIL-R1/TRAIL-R2, the T47D cell line required initial sensitization by doxorubicin and again exhibited selectivity towards apoptosis induced by a TRAIL-R1-selective ligand. Crucially, we show that doxorubicin can also sensitize TRAIL-resistant primary breast tumour explants to TRAIL-induced apoptosis, while having no effect on normal breast tissue. Furthermore, in this ex vivo model, TRAIL combined with doxorubicin induced significantly more apoptosis via TRAIL-R1 than TRAIL-R2.
Our results have important implications for the potential treatment of breast cancer with TRAIL-based therapeutic agents. We propose that using a TRAIL-R1-specific ligand/mAb combined with subtoxic concentrations of doxorubicin will selectively target tumour cells and minimise potential side effects, such as triggering of TRAIL-induced prosurvival pathways in TRAIL-resistant primary tumour cells or cardiotoxicity induced by higher concentrations of doxorubicin used in monotherapy.