1. Academic Validation
  2. OncomiR-10b hijacks the small molecule inhibitor linifanib in human cancers

OncomiR-10b hijacks the small molecule inhibitor linifanib in human cancers

  • Sci Rep. 2018 Aug 30;8(1):13106. doi: 10.1038/s41598-018-30989-3.
Paloma Del C Monroig-Bosque 1 2 Maitri Y Shah 1 Xiao Fu 1 3 Enrique Fuentes-Mattei 1 Hui Ling 1 4 Cristina Ivan 5 Nazila Nouraee 1 6 Beibei Huang 7 Lu Chen 7 Valentina Pileczki 1 8 Roxana S Redis 1 9 Eun-Jung Jung 1 10 Xinna Zhang 5 11 Michael Lehrer 1 Rahul Nagvekar 1 Ana Carolina P Mafra 1 12 Maria Del Mar Monroig-Bosque 1 13 Alexandra Irimie 1 14 Carlos Rivera 1 2 Calin Dan Dumitru 15 16 Ioana Berindan-Neagoe 8 17 Edward P Nikonowicz 18 Shuxing Zhang 7 George A Calin 19 20
Affiliations

Affiliations

  • 1 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 2 Department of Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico.
  • 3 Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 4 Cell & Gene Therapy, Bioverativ Inc. A Sanofi Company, Waltham, 02451, MA, USA.
  • 5 Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 6 Center for Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
  • 7 Intelligent Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 8 The Research Center for Functional Genomics, Biomedicine and Translational Medicine University of Medicine and Pharmacy 'I. Hatieganu', Cluj-Napoca, Romania.
  • 9 ProQR Therapeutics N.V., 2333 CK, Leiden, The Netherlands.
  • 10 Department of Surgery, School of Medicine, Gyeongsang National University, Jin-ju, South Korea.
  • 11 Medical and Molecular Genetics Department, Indiana University, Indianapolis, IN, USA.
  • 12 Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas - UNICAMP, Campinas, 13083-970, Sao Paulo, Brazil.
  • 13 Department of Biology, University of Puerto Rico, Mayaguez, Puerto Rico.
  • 14 Department of Dental Propaedeutics and Esthetics, Faculty of Dentistry, 'Iuliu Hatieganu' University of Medicine and Pharmacy, Cluj-Napoca, Romania.
  • 15 Scripps Laboratories for tRNA Synthetase Research, The Scripps Research Institute, La Jolla, California, USA.
  • 16 Translational Development and Diagnostics, Celgene Corporation, Summit, NJ, USA.
  • 17 Department of Functional Genomics and Experimental Pathology, The Oncology Institute "Prof. Dr. I Chiricuta", Cluj-Napoca, Romania.
  • 18 Department of Biochemistry and Cell Biology, Rice University, Houston, TX, USA.
  • 19 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [email protected].
  • 20 Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [email protected].
Abstract

The pervasive role of MicroRNAs (miRNAs) in Cancer pathobiology drives the introduction of new drug development approaches such as miRNA inhibition. In order to advance miRNA-therapeutics, meticulous screening strategies addressing specific tumor targets are needed. Small molecule inhibitors represent an attractive goal for these strategies. In this study, we devised a strategy to screen for small molecule inhibitors that specifically inhibit, directly or indirectly, miR-10b (SMIRs) which is overexpressed in metastatic tumors. We found that the multi-tyrosine kinase inhibitor linifanib could significantly inhibit miR-10b and reverse its oncogenic function in breast Cancer and liver Cancer both in vitro and in vivo. In addition, we showed that the efficacy of linifanib to inhibit tyrosine kinases was reduced by high miR-10b levels. When the level of miR-10b is high, it can "hijack" the linifanib and reduce its kinase inhibitory effects in Cancer resulting in reduced anti-tumor efficacy. In conclusion, our study describes an effective strategy to screen for small molecule inhibitors of miRNAs. We further propose that miR-10b expression levels, due to the newly described "hijacking" effect, may be used as a biomarker to select patients for linifanib treatment.

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