Use of Kinase Inhibitors to Illuminate Signaling Pathways in Breast Cancer

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Virginia Tech


In the United States, breast cancer is the most commonly diagnosed cancer and is the second most common cause of cancer-related deaths among women. Among the various subtypes of breast cancer, 25-30% of diagnoses present themselves as human epidermal growth factor receptor 2 positive (HER-2+). HER-2 is a protein receptor located on the cell surface that interacts with other proteins and signaling molecules to translate extracellular signals into cellular process such as cell growth and replication. However, in breast cancer, there is a drastic increase in the number of HER-2 proteins on the cell surface, that causes excessive cell growth and proliferation, and ultimately tumor formation. The most frequent treatment of HER-2+ breast cancers includes the use of a single agent inhibitor that directly blocks the HER-2 protein to prevent over-signaling and cell growth. However, after continuous use, breast cancer cells develop drug resistance, as other proteins such as the insulin-like growth factor 1 receptor (IGF-1R) and the protein kinase B (AKT) can also interfere and cause cell growth and replication. In this study, we propose that the use of a multi-agent treatment targeting the HER-2, IGF-1R, and AKT proteins will be more effective than a single-agent treatment of HER-2 alone. Through protein analysis by mass spectrometry, we intend to illuminate the different cellular responses to both treatment types. The results indicate that the single drug treatment targeting Her-2 appears to increase processes related cellular repair, while the multi-drug treatment indicates an increase in processes related to programmed cell death; both treatments appear to block the transmission of protein signaling.



breast cancer, SKBR3, mass spectrometry, proteomics, Lapatinib, Linsitinib, GDC-0068