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 cellcycle- targeting miRNAs for treatment of refractory cancer types.NIH [5 R01 CA083688, 5 R01 CA132740, 5 P01 CA080111]; Wennergren Foundations (Stockholm, Sweden); Peking-Tsinghua Center for Life Sciences; National Natural Science Foundation of China [71532001]; MNISW Fellowship; NovartisSCI(E)ARTICLE4576-+3