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HER2-positive breast cancer accounts for approximately 25-30% of all breast cancer cases, and carries a bad prognosis compared to HER2-negative breast cancer. Despite recent advances with the development of HER2-targeted treatments, mainly trastuzumab and lapatinib, there is universal development of drug resistance in patients with advanced HER2-positive breast cancer, and a high unmet medical need to develop new innovate drugs for these patients. Nelfinavir has been shown to have anticancer properties by inducing cellular endoplasmatic reticulum (ER) stress, and this effect can be potentiated by the combined administration of the proteasome inhibitor bortezomib. Carfilzomib is the first irreversible and highly potent proteasome inhibitor, that has recently been approved for refractory multiple myeloma by the FDA. Based on previous preclinical work in HER2-positive breast cancer, the combination of nelfinavir and carfilzomib is suggested to have substantial cytotoxic activity in HER2-positive breast cancer cells, primarily by inducing ER-stress and by the inhibition of AKT-signaling and heat-shock proteins. Accordingly, this study assesses the potential synergism of nelfinavir and carfilzomib in HER2-positive breast cancer cells, as this has not been explored so far. If successful, a phase 1 study will be planned in patients with advanced breast cancer to assess the clinical activity of this drug combination.