Activating Cell Death Pathways in Breast Cancer Cells

Division Of Clinical Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. TNF family death receptors (e.g., TNFR, Fas, DR3, TRAIL Receptor 1, and TRAIL Receptor 2) induce apoptosis in cells by recruiting and activating caspases upon activation by their respective ligands (e.g., TNF, Fas Ligand, and TRAIL). We are investigating the expression and function of TRAIL death receptors (members of the TNFR family) and their ligands (e.g., TRAIL and agonistic antibodies) in breast cancer cells in order to selectively trigger apoptosis in the cancer cells. In our early work, we found that most breast cancer cell lines are resistant to the induction of apoptosis by TRAIL. We have demonstrated that a subset of breast cancer cells, those with triple-negative/basal-like features are very sensitive to TRAIL-induced apoptosis while other breast cancer subtypes are relatively resistant to TRAIL-induced apoptosis. This subset of breast cancers is particularly aggressive and most in need of targeted therapies. Further, we found that TRAIL Receptor 2, and not TRAIL Receptor 1, is required for TRAIL induced apoptosis in the sensitive breast cancer cells. This latter finding will help in the selection of TRAIL agonists for eventual clinical trials in breast cancer patients. In addition, we have found that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents, targeted agents such as trastuzumab, and EGFR inhibitors. More recently, we have demonstrated that inhibition or loss of the G2/M checkpoint tyrosine kinase Wee1 enhances TRAIL-mediated apoptosis in basal-like breast cancer cells. Together these studies are beginning to provide clear preclinical rationales for studies of TRAIL ligands alone or in combination with other drugs in patients with breast cancer. Ongoing work is: 1) using functional genomics to identify and characterize the genes and proteins that regulate apoptosis induced by TRAIL receptor agonists in breast cancer cells. 2) characterizing novel TRAIL receptor agonists in breast cancer cells, 3) evaluating the effects on the immunogenecity of breast cancer cells. In a spin off projject we are characterizing the mechanism of action of ClpP agonists. The latter drug was described to work via the TRAIL pathway. However, our data suggest that it works independent of the TRAIL pathway to kill breast cancer and other cancer cells. Our ongoing work includes 1) characterizing the mchanism of death induced by ClpP agonists on breast cancer cells; 2) in collaboration with NCATS we conducted a screen to identify drugs that synergize with ClpP agonists in breast cancer cells and are validating hits from that screen to credential combination therapies that will be useful with ClpP agonists. 3) investigating the effects of ClpP agonists on breast cancer tumor initiating cells.