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

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. •Characterization of human microRNAs which target the cell-cycle machinery•Profiling cell-cycle-targeting miRNAs against 122 human cancer cell lines from CCLE•Algorithm to predict the response of tumors to cell-cycle-targeting miRNAs•In vivo delivery of cell-cycle-targeting miRNAs inhibits cancer growth 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.