Classically, investigations of drug resistance in hematopoietic malignancies have focused on in vitro selection from drug resistant populations following chronic exposure to cytotoxic drugs. These studies have demonstrated that acquired drug resistance is due to multiple factors including over-expression of MDR1/P-glycoprotein, alterations in drug target, and repair of cellular damage. While these acquired mechanisms contribute to the overall drug resistant phenotype, it is unlikely that they determine initial drug response. Little is known about how cancer cells survive initial cytotoxic drug exposure and eventually select for drug resistant populations. Factors that allow for cell survival following initial drug exposure and eventually select for drug resistant populations. Factors that allow for cell survival following initial drug exposure need to be identified, because such factors may eventually allow for expression of genes associated with acquired drug resistance. Because most mechanisms of acquired drug resistance have been discovered using in vitro cell lines, the tumor cell-response in tumor cells by preventing drug- induced apoptosis and eventually allows for the acquisition of classical drug resistance mechanisms. We have preliminary evidence demonstrating that myeloma cell interaction with fibronectin (FN) and collagen I, reduces cytotoxic drug-induced apoptosis. We have used the term """"""""cell adhesion mediated drug resistance"""""""" or CAM-DR to describe this phenomenon. Planned experiments are based on the following three main observations: (1) Cellular adhesion and beta1 integrin activation blocks drug-induced apoptosis, (2) cellular adhesion induces cell cycle arrest associated with increased p27/Kip1 protein levels, and (3) drug induced DNA damage is reduced when cells are adhered to FN. In the first specific aim of this project we will analyze signal transduction pathways activated by the integrin receptors, VLA-4 and VLA-5.
In specific aim 2, we will analyze how cellular adhesion results in cell cycle arrest and whether this is a necessary component of CAM-DR. In specific 3, we will examine the role of DNA-PK as a critical mediator of drug induced DNA damage to adherent vs. non-adherent cells. And finally, the fourth specific aim will identify agents that disrupt tumor cell microenvironment interactions in attempts to prevent or overcome CAM-DR. Identifying factors that influence initial drug response and eventual emergence of drug resistance will provide new approaches to improving therapeutic outcome of myeloma, and other cancers.
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