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

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.

• Authors: Paloma Del C Monroig-Bosque, Maitri Y Shah, Xiao Fu, Enrique Fuentes-Mattei, Hui Ling, Cristina Ivan, Nazila Nouraee, Beibei Huang, Lu Chen, Valentina Pileczki, Roxana S Redis, Eun-Jung Jung, Xinna Zhang, Michael Lehrer, Rahul Nagvekar, Ana Carolina P Mafra, Maria Del Mar Monroig-Bosque, Alexandra Irimie, Carlos Rivera, Calin Dan Dumitru, Ioana Berindan-Neagoe, Edward P Nikonowicz, Shuxing Zhang, George A Calin
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 13106 (08 30 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 30166612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Indazoles
• MIRN10 microRNA, human
• MicroRNAs
• Phenylurea Compounds
• RNA, Neoplasm
• linifanib

Topics

• Breast Neoplasms (drug therapy, metabolism, pathology)
• Drug Resistance, Neoplasm
• Female
• Hep G2 Cells
• Humans
• Indazoles (pharmacology)
• Liver Neoplasms (drug therapy, metabolism, pathology)
• MCF-7 Cells
• Male
• MicroRNAs (metabolism)
• Neoplasm Metastasis
• Phenylurea Compounds (pharmacology)
• RNA, Neoplasm (metabolism)