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

  • Cancer Cell. 2017 Apr 10;31(4):576-590.e8. doi: 10.1016/j.ccell.2017.03.004.
Per Hydbring  1 ,  Yinan Wang  2 ,  Anne Fassl  3 ,  Xiaoting Li  4 ,  Veronica Matia  3 ,  Tobias Otto  3 ,  Yoon Jong Choi  3 ,  Katharine E Sweeney  3 ,  Jan M Suski  3 ,  Hao Yin  5 ,  Roman L Bogorad  5 ,  Shom Goel  6 ,  Haluk Yuzugullu  7 ,  Kevin J Kauffman  5 ,  Junghoon Yang  5 ,  Chong Jin  2 ,  Yingxiang Li  8 ,  Davide Floris  3 ,  Richard Swanson  9 ,  Kimmie Ng  10 ,  Ewa Sicinska  11 ,  Lars Anders  12 ,  Jean J Zhao  7 ,  Kornelia Polyak  13 ,  Daniel G Anderson  14 ,  Cheng Li  15 ,  Piotr Sicinski  16
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA; Department of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, Sweden.
  • 2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, Center for Life Sciences and Center for Statistical Science, Peking University, Beijing 100871, China.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA.
  • 4. School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 5. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 6. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 7. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 8. Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
  • 9. Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 10. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 11. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 12. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 13. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
  • 14. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Harvard-MIT Division of Health Sciences & Technology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 15. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, Center for Life Sciences and Center for Statistical Science, Peking University, Beijing 100871, China. Electronic address: [email protected].
  • 16. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
PMID: 28399412 DOI: 10.1016/j.ccell.2017.03.004
Abstract

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.

Keywords
cancers; cell cycle; cyclin-dependent kinases; cyclins; microRNAs.
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