PDX Pharmaceuticals, in collaboration with the Biomedical Engineering Department of Oregon Health and Science University, has developed PDX-001 as a targeted nanoparticle for delivery of therapeutic siRNA for treating HER2+ breast cancer. The work has been funded by fast-track phase I/II SBIR awards from the NIH/NCI as well as angel funds (the Prospect Creek Foundation and Schwab Charitable Trust). We report on a long-term treatment study of therapeutic HER2 siRNA using PDX-001. We have shown that unlike trastuzumab (monoclonal antibody) and lapatinib (small molecule inhibitor), which induced resistance in HER2-positive cells after 6 months of treatment, HER2 siRNA delivered using PDX-001, did not induce resistance to HER2 siRNA, trastuzumab, or lapatinib. In addition, the treated cells did not undergo epithelial-mesenchymal transition or showed enrichment of tumor initiating cells. Altogether, our results indicate that a HER2 siRNA based therapeutic provides a more durable inhibition of HER2 signaling in vitro and can potentially be more effective than the existing therapeutic monoclonal antibodies and small molecule inhibitors.