Please cite this article in press as: Giovannetti E, et al. Molecular mechanisms underlying the role of microRNAs (miRNAs) in anticancer drug resistance and implications for clinical practice. Crit Rev Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2011.03.010 ARTICLE IN PRESS ONCH-1532; No. of Pages 20 Critical Reviews in Oncology/Hematology xxx (2011) xxx–xxx Molecular mechanisms underlying the role of microRNAs (miRNAs) in anticancer drug resistance and implications for clinical practice Elisa Giovannetti a,b,∗ , Ayse Erozenci a , Jorn Smit a , Romano Danesi b , Godefridus J. Peters a a VU University Medical Center, Amsterdam, The Netherlands b Department Internal Medicine, University of Pisa, Pisa, Italy Accepted 31 March 2011 Contents 1. Introduction ........................................................................................................... 00 1.1. miRNAs and cancer ............................................................................................. 00 1.2. miRNAs and anticancer drug resistance ........................................................................... 00 2. Deregulation of miRNA expression and drug resistance ................................................................... 00 2.1. miRNA-mediated modulation of survival and/or apoptosis pathways ................................................. 00 2.2. miRNA-mediated modulation of drug targets and DNA repair ....................................................... 00 2.3. miRNA-mediated modulation of drug transport and metabolism ..................................................... 00 2.4. miRNA pharmacogenetics and drug resistance ..................................................................... 00 3. miRNAs in cancer stem cells and drug resistance ......................................................................... 00 3.1. Role of miRNA in stem cells and cancer stem cells (CSCs) .......................................................... 00 3.2. Role of miRNA in CSC drug resistance ............................................................................ 00 4. miRNAs as predictors of drug resistance and clinical outcome in pancreatic and lung cancers ................................. 00 5. Conclusions and future prospectives ..................................................................................... 00 Reviewers ............................................................................................................ 00 Conflict of interest ..................................................................................................... 00 Acknowledgement ..................................................................................................... 00 References ............................................................................................................ 00 Biographies ........................................................................................................... 00 Abstract Drug resistance remains a major problem in the treatment of cancer patients for both conventional chemotherapeutic and novel biological agents. Intrinsic or acquired resistance can be caused by a range of mechanisms, including increased drug elimination, decreased drug uptake, drug inactivation and alterations of drug targets. Recent data showed that other than by genetic (mutation, amplification) and epigenetic (DNA hypermethylation, histone post-translational modification) changes, drug resistance mechanisms might also be regulated by microRNAs (miRNAs). In this review we provide an overview on the role of miRNAs in anticancer drug resistance, reporting the main studies on alterations in cell survival and/or apoptosis pathways, as well as in drug targets and determinants of drug metabolism, mediated by deregulation of miRNA expression. The current status of pharmacogenetic studies on miRNA and their possible role in cancer stem cell drug resistance are also discussed. Finally, we integrated the preclinical data with clinical evidences, in lung and pancreatic cancers, showing how the study of ∗ Corresponding author at: Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel.: +31 20 4442267; fax: +31 20 4443844. E-mail address: elisa.giovannetti@gmail.com (E. Giovannetti). 1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2011.03.010