This research program is focused on the development of drug combinations for use in patients with relapsed breast cancer. More specifically, a significant number of women suffer from advanced breast cancers that express HER-2, a protein that is associated with more aggressive metastatic breast cancer. Trastuzumab is a drug specifically designed to treat individuals with HER-2 positive disease. Unfortunately, many patients who initially respond, when first treated with trastuzumab, will relapse with a disease that will be resistant to this drug. Therefore, we need to develop new effective drugs for this group of patients. The goal of this research program is to gain new insights into the mechanisms contributing to the behavior of HER-2 positive cancers when initially exposed to different drugs and learn how to fight these mechanisms to make treatments more effective and avoid problems with drug resistance. Here, we propose two research approaches. The first one is focused on addressing a transient (reversible) adaptive response called autophagy, a cellular mechanism protecting the cancer cells from cell death while treated with anti-cancer drugs. The studies proposed here will determine whether improved treatment responses can be achieved when we combine drugs that inhibit this protective response. The second goal is designed to identify other protective responses in HER-2 positive breast cancer cells that occur when they are first exposed to selected drugs. Once these protective responses are understood, then, genes or products of these genes, will be identified as new targets for treatment. Drugs against these targets would be extremely valuable when used in a combination with the agents that first elicited the protective response of cancer cells.