The her2 gene is overexpressed in approximately 30% of metastatic breast cancers, and is associated with rapid disease progression and reduced overall survival. The median duration of response to the HER2-targeted drug Herceptin is less than one year, indicating that acquired drug resistance is a major clinical problem in the treatment of HER2-overexpressing metastatic breast cancer. The long-term goal of this application is to identify mechanisms and predictors of Herceptin resistance in order to improve the survival of patients with HER2-overexpressing breast cancer. Herceptin-resistant cells express reduced levels of the cyclin-dependent kinase (cdk) inhibitor p27 and show a unique receptor cross-talk between insulin-like growth factor-I receptor (IGF-IR), HER2, and HER3. Our central hypothesis is that the IGF-IR/HER2/HER3 complex activates downstream kinase signaling pathways that promote phosphorylation and degradation of p27, causing increased proliferation of HER2-overexpressing breast cancer cells. Using a particularly innovative multidisciplinary approach that combines nanotechnology, genetics, and pharmacology, we will determine (1) the mechanisms by which p27 is down- regulated in acquired Herceptin resistance, (2) the role of the IGF-IR/HER2/HER3 receptor complex in acquired Herceptin resistance, and (3) if IGF-IR, HER3, and FAK are in vivo targets for improving response to Herceptin. Access to multiple models of acquired Herceptin resistance and multiple patient tumor tissue sets places us in a unique position to discover novel therapeutic targets and markers of resistance. Ultimately, this study will benefit human health by identifying new molecular targets, novel drug combinations, and molecular markers of drug resistance in HER2-overexpressing breast cancer. Understanding the mechanisms leading to acquired Herceptin resistance will ultimately lead to refined therapeutic strategies and improved survival rates for patients with breast cancer.
Resistance to the HER2-targeted drug Herceptin is a major problem in the treatment of breast cancer. We will examine how IGF-IR and p27 regulation contribute to Herceptin resistance. The long-term goal of this application is to identify new drug targets and predictors of Herceptin resistance in order to improve the survival of patients with HER2-overexpressing breast cancer.
|Paplomata, Elisavet; Nahta, Rita (2018) ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer. Expert Opin Biol Ther 18:335-341|
|O'Regan, Ruth M; Nahta, Rita (2018) Targeting forkhead box M1 transcription factor in breast cancer. Biochem Pharmacol 154:407-413|
|Peake, Bridgette F; Eze, Siobhan M; Yang, Lily et al. (2017) Growth differentiation factor 15 mediates epithelial mesenchymal transition and invasion of breast cancers through IGF-1R-FoxM1 signaling. Oncotarget 8:94393-94406|
|Taliaferro-Smith, LaTonia; Oberlick, Elaine; Liu, Tongrui et al. (2015) FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells. Oncotarget 6:4757-72|
|Overholser, Jay; Ambegaokar, Kristen Henkins; Eze, Siobhan M et al. (2015) Anti-Tumor Effects of Peptide Therapeutic and Peptide Vaccine Antibody Co-targeting HER-1 and HER-2 in Esophageal Cancer (EC) and HER-1 and IGF-1R in Triple-Negative Breast Cancer (TNBC). Vaccines (Basel) 3:519-43|
|Nahta, Rita; Al-Mulla, Fahd; Al-Temaimi, Rabeah et al. (2015) Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression. Carcinogenesis 36 Suppl 1:S2-18|
|Sanabria-Figueroa, Eduardo; Donnelly, Siobhan M; Foy, Kevin C et al. (2015) Insulin-like growth factor-1 receptor signaling increases the invasive potential of human epidermal growth factor receptor 2-overexpressing breast cancer cells via Src-focal adhesion kinase and forkhead box protein M1. Mol Pharmacol 87:150-61|
|Peake, Bridgette F; Nahta, Rita (2014) Resistance to HER2-targeted therapies: a potential role for FOXM1. Breast Cancer Manag 3:423-431|
|Donnelly, S M; Paplomata, E; Peake, B M et al. (2014) P38 MAPK contributes to resistance and invasiveness of HER2- overexpressing breast cancer. Curr Med Chem 21:501-10|
|Griner, Samantha E; Wang, Katherine J; Joshi, Jayashree P et al. (2013) Mechanisms of Adipocytokine-Mediated Trastuzumab Resistance in HER2-Positive Breast Cancer Cell Lines. Curr Pharmacogenomics Person Med 11:31-41|
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