Septins disruption controls tumor growth and enhances efficacy of Herceptin

Singh, R. K.; Kim, K. K.; Khazan, N.; Rowswell_Turner, R. B.; Laggner, C.; Jones, A.; Srivastava, P.; Hovanesian, V.; Lamere, L.; Conley, T.; Pandita, R.; Baker, C.; Myers, J. R.; Prichett, E.; Awada, A.; Ruffolo, L.; Jackson, C.; Gerber, S.; Ashton, J.; Milano, M. T.; Linehan, D.; Moore, R.

doi:10.1101/2020.02.19.954529

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bioRxiv · 10.1101/2020.02.19.954529

Septins disruption controls tumor growth and enhances efficacy of Herceptin

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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.

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Singh, R. K., Kim, K. K., Khazan, N., Rowswell_Turner, R. B., Laggner, C., Jones, A., Srivastava, P., Hovanesian, V., Lamere, L., Conley, T., Pandita, R., Baker, C., Myers, J. R., Prichett, E., Awada, A., Ruffolo, L., Jackson, C., Gerber, S., Ashton, J., Milano, M. T., Linehan, D., Moore, R.. 2020-02-20. Septins disruption controls tumor growth and enhances efficacy of Herceptin. https://doi.org/10.1101/2020.02.19.954529

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