Abstract
BackgroundResearch is revealing the complex coordination between cell signaling systems as they adapt to genetic and epigenetic changes. Tools to uncover these highly complex functional linkages will play an important role in advancing more efficacious disease treatments. Current tumor cell signal transduction research is identifying coordination between receptor types, receptor families, and transduction pathways to maintain tumor cell viability despite challenging tumor microenvironment conditions.MethodsIn this report, coactivated abnormal levels of signaling activity for c-Met and HER family receptors in live tumor cells were measured by a new clinical test to identify a subpopulation of breast cancer patients that could be responsive to combined targeted therapies. The CELsignia Multi-Pathway Signaling Function (CELsignia) Test uses an impedance biosensor to quantify an individual patient’s ex vivo live tumor cell signaling response in real-time to specific HER family and c-Met co-stimulation and targeted therapies.ResultsThe test identified breast tumors with hyperactive HER1, HER2, HER3/4, and c-Met coordinated signaling that express otherwise normal amounts of these receptors. The supporting data of the pre-clinical verification of this test included analyses of 79 breast cancer patients’ cell response to HER and c-Met agonists. The signaling results were confirmed using clinically approved matching targeted drugs, and combinations of targeted drugs in addition to correlative mouse xenograft tumor response to HER and c-Met targeted therapies.ConclusionsThe results of this study demonstrated the potential benefit of a functional test for identifying a subpopulation of breast cancer patients with coordinated abnormal HER and c-Met signaling for a clinical trial testing combination targeted therapy.4ydEpWcWmteHkpnJtfDHYnVideo
Highlights
Research is revealing the complex coordination between cell signaling systems as they adapt to genetic and epigenetic changes
Other studies have demonstrated the possibility for Comparison of expression levels of hepatocyte growth factor (HGF) receptor (c-Met) and human epidermal growth factor receptor (HER) family activation to participate in mitogen activated protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K) pathway extensive interactions that drive cancer progression [9,10,11]
To elucidate the role of c-Met signaling and its involvement with HER family signaling as a cancer co-driver, a new test was developed based on the principle of tumor cell impedance alterations from hypersignaling as described previously for patients that we demonstrated do not have overexpressed receptors
Summary
Research is revealing the complex coordination between cell signaling systems as they adapt to genetic and epigenetic changes Tools to uncover these highly complex functional linkages will play an important role in advancing more efficacious disease treatments. Other studies have demonstrated the possibility for c-Met and HER family activation to participate in mitogen activated protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K) pathway extensive interactions that drive cancer progression [9,10,11]. These studies and proposed coordination mechanisms have led to clinical testing of drug combinations in patients with various solid tumor types. Detection of c-Met expression level by immunohistochemical (IHC) analysis as a clinical pathology diagnostic marker has failed to accurately identify a population responsive to c-Met targeted therapies, suggesting an alternative approach is required to identify patients with dysfunctional HER and c-Met signaling who will respond to these therapies
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