Distinct growth factor-induced dynamic mass redistribution (DMR) profiles for monitoring oncogenic signaling pathways in various cancer cells

Abstract

Targeting dysregulated signaling pathways in tumors has led to the development of a novel class of signal transduction inhibitors, including inhibitors of the epidermal growth factor (EGF) receptor (EGFR). To dissect oncogenic pathways, identify key pathway determinants, and evaluate the efficacy of targeted agents, it is vital to develop technologies that allow the detection of temporal signaling events under physiological conditions. Here we report the application of a label-free optical biosensor to reveal the rapid response of cancer cells to EGF, expressed as a dynamic mass redistribution (DMR) signal. In response to EGF, squamous cell carcinoma of the head and neck cells exhibited a rapid rise in DMR signal, whereas lung adenocarcinoma cells showed a biphasic DMR profile, suggesting a cell type-dependent DMR response. Pharmacological studies suggested the importance of EGFR and the phosphatidylinositol-3 kinase pathway in mediating the EGF-induced DMR response. The defined DMR signatures offer a simple yet sensitive tool for evaluating EGFR-targeted agents, as shown with gefitinib and erlotinib. The assay can also be used for cell-based high-throughput screening of EGF pathway inhibitors, as demonstrated by its robust performance in a 384-well plate format (Z′ > 0.5). This technology is applicable to other oncogenic pathways for the discovery of novel therapeutic agents for the treatment of various cancers.

Keywords::

• Label-free
• epidermal growth factor (EGF) receptor
• dynamic mass redistribution (DMR)
• oncogenic pathway
• high-throughput screening

Acknowledgments

This research was supported by the National Institutes of Health grant 5 P50 CA128613 SPORE in Head and Neck Cancer (YD, ZGC, SYS, DMS, FRK, and HF) P01 CA116676 Lung Cancer Program (FRK, HF), and 5U54 HG003918 Emory Chemical Biology Discovery Center in MLSCN (HF). ZJL is an Emory Global Health Institute-Peking University Health Science Center exchange scholar. YD is a recipient of Emory University’s SPORE in Head and Neck Cancer Career Development award (P50 CA128613). HF is a Georgia Research Alliance Distinguished Investigator. DMS, FRK, HF and ZGC are Georgia Cancer Coalition Distinguished Cancer Scholars.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.