Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers

Publication date: 10 April 2017
Source:Cancer Cell, Volume 31, Issue 4
Author(s): Per Hydbring, Yinan Wang, Anne Fassl, Xiaoting Li, Veronica Matia, Tobias Otto, Yoon Jong Choi, Katharine E. Sweeney, Jan M. Suski, Hao Yin, Roman L. Bogorad, Shom Goel, Haluk Yuzugullu, Kevin J. Kauffman, Junghoon Yang, Chong Jin, Yingxiang Li, Davide Floris, Richard Swanson, Kimmie Ng, Ewa Sicinska, Lars Anders, Jean J. Zhao, Kornelia Polyak, Daniel G. Anderson, Cheng Li, Piotr Sicinski
Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in numerous human tumors. To identify means of interfering with cyclins/CDKs, we performed nine genome-wide screens for human microRNAs (miRNAs) directly regulating cell-cycle proteins. We uncovered a distinct class of miRNAs that target nearly all cyclins/CDKs, which are very effective in inhibiting cancer cell proliferation. By profiling the response of over 120 human cancer cell lines, we derived an expression-based algorithm that can predict the response of tumors to cell-cycle-targeting miRNAs. Using systemic administration of nanoparticle-formulated miRNAs, we inhibited tumor progression in seven mouse xenograft models, including three treatment-refractory patient-derived tumors, without affecting normal tissues. Our results highlight the utility of using cell-cycle-targeting miRNAs for treatment of refractory cancer types.

Teaser

By performing screens for miRNAs targeting cell-cycle proteins, Hydbring et al. identify a class of miRNAs that target multiple cyclins and CDKs. Nanoparticle delivery of these miRNAs inhibits tumor growth in several xenograft models, including treatment-refractory patient-derived xenografts.


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