Welcome to the laboratory of Ron Bose, MD, PhD,
at Washington University School of Medicine in St. Louis, MO.
HER2 receptor tyrosine kinase signaling in human cancers
Dysregulation of signal transduction pathways plays a major role in the development of human cancers. We focus on the HER2 receptor tyrosine kinase, a member of the EGFR growth factor receptor family, which is gene amplified and activated in about 20% of human breast cancer cases. HER2 is a very important drug target, and there are four FDA-approved drugs commonly used in oncology clinics to bind and inhibit it. We discovered that HER2 activating mutations can be found in many solid tumors, including breast cancer. The major clinical implication of this finding is: Patients with HER2 mutation positive cancers could benefit from the existing, FDA-approved anti-HER2 drugs.
Our lab studies signal transduction pathways in breast cancer using a variety of approaches involving cancer biology, biochemistry, next-generation DNA sequencing, mass spectrometry, and mouse models. Fundamental questions that we are interested in are:
- What are the mechanisms that activate and regulate HER2?
- How do genomic alterations in HER2 contribute to breast cancer and other human cancers?
- How does HER2 cooperate with other genes to form cancers?
- What are the most effective strategies to treat HER2 mutation positive cancers?
Research in the Bose lab is divided into the following project areas:
Project Area 1: Functional Studies on HER2 Mutations Found in Human Cancers.
We introduce HER2 mutations into cancer cell lines and immortalized, but non-transformed epithelial cell lines using retroviral vectors. The effects of HER2 mutations on signaling pathways, anchorage-independent cell growth, growth in 3D culture, drug sensitivity or resistance, and tumor formation in mouse xenografts are then measured.
Project Area 2: HER2 driven Mouse Models of Cancer.
By performing proteomics on an established HER2 mutant transgenic mouse, we mapped the signaling pathways activated in situ by HER2. Next, we defined the time course and pattern of development of pre-invasive and invasive breast cancer in these mice. Using new transgenic lines and patient derived xenografts (PDX), we will study the interactions between HER2 mutations and other genes and determine the drug sensitivity of the resulting tumors. PDX’s have the advantage that they are the closest experimental model to human cancers and that genetic drift between the primary cancer and the PDX is minimized. However, PDX’s are very hard to genetically manipulate and must be grown in immunocompromised mice, which generally makes immunotherapy experiments impossible. Transgenic mice models are able to complement PDX models, because of the relative ease of genetic manipulation, presence of an intact immune system, and the ability to perform immunotherapy studies. A combination of transgenic mice and PDX offers a powerful way to study human cancers.
Project Area 3: HER2 Protein Structure and Function.
This project uses in vitro biochemistry and structural biology experiments to define the mechanisms of activation and regulation of the HER2 and HER4 kinases. Using protein mass spectrometry, FRET, and biochemical and biophysical techniques, we are studying the molecular mechanisms that regulate the activation of the HER2 tyrosine kinase. We are measuring the affinity of HER2 dimerization, interactions between various domains of HER2, and HER2’s interactions with its family members.
Please come talk to me to get more details about this research. I am very interested in having new post-doctoral fellows, graduate students, and undergraduates come to the lab.
updated March 10, 2017.