Project description:Estrogen receptor positive (ER+) breast cancers that develop resistance to therapies that target the ER are the most common cause of breast cancer death. Beyond mutations in ER, which occur in 25-30% of patients treated with aromatase inhibitors (AIs), our understanding of clinical mechanisms of resistance to ER-directed therapies remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER+ metastatic breast cancer who had developed resistance to ER-directed agents, including AIs, tamoxifen, and fulvestrant. Examination of treatment-naïve primary tumors in five patients revealed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. These mutations were mutually exclusive with ER mutations, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that these mutations conferred estrogen independence. In addition, and in contrast to ER mutations, these mutations resulted in resistance to tamoxifen, fulvestrant, and the CDK4/6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib, highlighting an effective treatment strategy in these patients.
Project description:The nucleolus, responsible for ribosome biogenesis, acts as a key center for detecting and responding to cellular stress. Additionally, growing evidence suggests that ribosome biogenesis may play a significant role in promoting metastasis. A proteomic screen of nucleolar protein content between metastatic and non-metastatic breast cancers found that metastatic breast cancer cell lines have a unique nucleolar proteome signature as compared to non-metastatic breast cancer cell lines.
Project description:Identify therapeutic vulnerabilities of palbociclib resistance in metastatic breast cancer patient-derived xenograft models and identify key biomarkers that correlate with development of resistance to inform new treatment directions