Approximately 15-20% of breast cancer patients are diagnosed with human epidermal growth factor receptor type 2 (HER2) amplification or overexpression and are at a greater risk for disease progression and poor clinical outcome. HER2, therefore, represents an attracted target for pharmacological intervention. At present, there are two HER2-targeted therapies approved for the treatment of HER2-positive breast cancer including trastuzumab (a therapeutic antibody) and lapatinib (a small molecule inhibitor). These HER2-targeted therapies have shown clinical activity alone or in combination with chemotherapy, and clinical trials are underway to explore the combination of trastuzumab and lapatinib together. However, many patients would relapse during the course of treatment, suggesting the existence of intrinsic or acquired resistance to these two HER2-targeted therapies. In my research study, I will try to identify the resistance mechanisms to trastuzumab and lapatinib via genome-wide lentiviral shRNA screens. The resistance-conferring genes identified from trastuzumab and lapatinib screens will be analyzed to find if any common resistance-conferring pathways exist. If successful, I will further investigate the efficacy of therapeutically targeting these pathways along with trastuzumab and/or lapatinib. My proposed research study has the potential to provide a genome-wide identification of resistance mechanisms to the two currently approved HER2-targeted therapies. The insights gained from my study may be applied to guide the development of novel treatment combination to treat HER2-positive breast cancer.