Year: 2020
Type: preprint
Abstract: Septin expressions are altered in cancer cells and exhibit poor prognoses in malignancies. As the first approach to develop a septin filament targeting agent, we optimized the structure of Forchlorfenuron (FCF), a known plant cytokinin to generate UR214-9, which contrary to FCF, causes septin-2/9 filamental structural catastrophe in cancer cells without altering cellular septin protein levels. In-silico docking using septin-2/septin-2 dimer complex showed that UR214-9 displaced the guanine carbonyl oxygen from the GDP binding domain and showed increased binding energy than FCF(−8.59vs-7.21). UR214-9 reduced cancer cell growth, downregulated HER2/STAT-3 axis and controlled growth of HER2+ pancreatic, breast and ovarian cancer xenografts in NSG mice and enhanced response of Herceptin against HER2+breast cancer xenograft. Transcriptome analysis of UR214-9 exposed cells demonstrated significant perturbation of <20 genes compared to afatinib which impacted >1200 genes in JIMT-1 breast cancer cells indicating target specificity and non-transcriptional functions of UR214-9. In summary, disrupting septins via UR214-9 is a new approach to control the growth of HER2+ malignancies.
Authors: Rakesh K Singh, Kyu Kwang Kim, Negar Khazan, Rachael B. Rowswell-Turner, Christian Laggner, Aaron Jones, Priyanka Srivastava, Virginia Hovanesian, Liz Lamere, Thomas Conley, Ravina Pandita, Cameron Baker, Jason R Myers, Elizabeth Pritchett, Awada Ahmad, Luis Ruffolo, Katherine Jackson, Scott A. Gerber, John Ashton, Michael T. Milano, David Linehan, Richard G Moore
Language: English
Topic: HER2/EGFR in Cancer Research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: University of Rochester
OpenAlex ID: W3008074616