Dynamin impacts homology-directed repair and breast cancer response to chemotherapy

Sophia B. Chernikova, Rochelle B. Nguyen, Jessica T. Truong, Stephano S. Mello, Jason H. Stafford, Michael P. Hay, Andrew Olson, David E. Solow-Cordero, Douglas J. Wood, Solomon Henry, Rie von Eyben, Lei Deng, Melanie Hayden Gephart, Asaithamby Aroumougame, Claudia Wiese, John C. Game, Balázs Győrffy, J. Martin Brown

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Abstract

After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapy-resistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor–negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy.

Original languageEnglish (US)
Pages (from-to)5307-5321
Number of pages15
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
StatePublished - Dec 3 2018

ASJC Scopus subject areas

  • Medicine(all)

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    Chernikova, S. B., Nguyen, R. B., Truong, J. T., Mello, S. S., Stafford, J. H., Hay, M. P., Olson, A., Solow-Cordero, D. E., Wood, D. J., Henry, S., von Eyben, R., Deng, L., Gephart, M. H., Aroumougame, A., Wiese, C., Game, J. C., Győrffy, B., & Martin Brown, J. (2018). Dynamin impacts homology-directed repair and breast cancer response to chemotherapy. Journal of Clinical Investigation, 128(12), 5307-5321. https://doi.org/10.1172/JCI87191