TY - JOUR
T1 - OncomiR-10b hijacks the small molecule inhibitor linifanib in human cancers
AU - Monroig-Bosque, Paloma del C.
AU - Shah, Maitri Y.
AU - Fu, Xiao
AU - Fuentes-Mattei, Enrique
AU - Ling, Hui
AU - Ivan, Cristina
AU - Nouraee, Nazila
AU - Huang, Beibei
AU - Chen, Lu
AU - Pileczki, Valentina
AU - Redis, Roxana S.
AU - Jung, Eun Jung
AU - Zhang, Xinna
AU - Lehrer, Michael
AU - Nagvekar, Rahul
AU - Mafra, Ana Carolina P.
AU - Monroig-Bosque, Maria del Mar
AU - Irimie, Alexandra
AU - Rivera, Carlos
AU - Dan Dumitru, Calin
AU - Berindan-Neagoe, Ioana
AU - Nikonowicz, Edward P.
AU - Zhang, Shuxing
AU - Calin, George A.
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41598-018-30989-3
DO - 10.1038/s41598-018-30989-3
M3 - Article
C2 - 30166612
AN - SCOPUS:85052714911
SN - 2045-2322
VL - 8
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 13106
ER -