Despite considerable success in developing novel
targeted therapies drug resistance is still the largest obstacle for more
effective management of cancer. For many types of cancer there is also paucity
of clearly defined molecular targets, and chemotherapy remains the only
treatment option available. This calls for rethinking of how we study cancer
chemoresistance and for devising alternative treatment strategies, enabling
better treatment outcomes. MicroRNAs are small non-coding RNAs able to
simultaneously regulate hundreds of targets that operate within complex
functional programs important for cancer development and maintenance. MicroRNA-based
drugs therefore represent an exciting new therapy approach, and several
microRNA mimics and inhibitors have been successfully tested in clinical
trials. Here we employ functional genomics to search for the most potent
microRNA candidates that either kill cancer cells on their own or synergise
with different chemotherapeutic drugs. We performed genome-wide inhibition and
overexpression of ~1500 microRNAs in breast cancer, neuroblastoma, and prostate
cancer models in vitro, in the
presence of common molecularly distinct chemotherapeutic drugs. Cell viability
measurements revealed numerous cell-type- and drug-type-specific synthetic
lethal interactions between the microRNAs and chemotherapy. Different
functional assays, in addition, enabled us to pinpoint the exact cellular
processes—such as apoptosis, proliferation, or DNA damage—that underlie these
effects. Finally, to search for direct microRNA targets, we measured changes in
gene expression in cells expressing candidate microRNA mimics and constructed
novel tools for microRNA target prediction and prioritisation. This approach
identified several strong candidates, which we are currently pursuing in vivo using an innovative method of targeted
drug delivery. We believe that our comprehensive and integrative analysis of
microRNA function will be an important resource both for studying the mechanism
of drug resistance and for identifying the most effective microRNA-based
combination therapies.