The primary focus of our research involves the examination and treatment of growth factor alterations in breast cancer, particularly the human epidermal growth factor receptor 2 (HER2, also known as HER2/neu). The her-2 gene is amplified in approximately 20% of invasive breast cancers, and its overexpression is associated with poor prognosis. Interference with HER2 function using monoclonal antibodies (e.g., trastuzumab) or small molecule tyrosine kinase inhibitors (e.g., lapatinib) is a validated therapeutic strategy in women with HER2-positive breast cancer. However, primary or acquired resistance to HER2 targeted therapy remains a significant clinical problem. Using breast cancer cell lines, animal models and patient samples, our group identified PTEN loss and hyperactivation of the PI3K pathway as a mechanism of resistance to trastuzumab in HER2-overexpressing breast cancer. We translated our discoveries to the clinic by combining trastuzumab with the mTOR inhibitor everolimus (RAD001) and showed that trastuzumab resistance can be overcome by this approach in breast cancer patients whose tumors had progressed on trastuzumab. Another mechanism of escape to trastuzumab is the activation of insulin-like growth factor receptor I (IGF-IR) signaling. Our laboratory showed that HER2/IGF-IR heterodimerization occurs in cell lines selected for trastuzumab resistance after long exposure in vitro, but not in parental, trastuzumab-sensitive breast cancer cell lines. Our preclinical data support the clinical development of HER2 and IGF-IR inhibitors in combination as a potential novel strategy for HER2-overexpressing breast cancer. Combining therapeutic agents directed against the same genetic alteration may be a viable strategy in oncology. For example, our laboratory showed that a combination of two monoclonal antibodies raised against different epitopes of the HER2 extracellular domain results in synergistic induction of apoptosis in HER2-overexpressing breast cancer cell lines. Our long-term goal is to understand molecular mechanisms of drug resistance in the laboratory and overcome resistance in breast cancer patients.
Francisco J. Esteva, MD, PhD