Despite continuing advances in the identification of new targets for cancer therapy, many approaches show modest clinical benefits, induce a response only in a portion of the patients, and/or become inefficient after patients develop drug resistance. New approaches are therefore needed to overcome these effects. There is tremendous optimism regarding the potential of RNA-based therapies where oncogenes could be suppressed by small non-coding RNAs (specifically, siRNAs and miRNAs). However, the problem of off-target effects persists. We have found that by combining small RNAs, a synergistic action emerges such that they are effective even at very low concentrations where off-target effects are minimal and widely distributed across the transcriptome.
Here we select small RNAs to target simultaneously the main components of the RAS-MAPK pathway, a cell signalling cascade that governs cell survival and is often dysregulated in cancer through genetic alteration. We show that combining these small RNAs at sub-nanomolar levels efficiently reduces the activity of the RAS-MAPK pathway and specifically decreases the survival of RAS-dependent melanoma cells, even if they are already resistant to targeted therapy. The next step will be to confirm the effectiveness of this strategy on tumour growth in vivo.
This work provides proof of principle for a new pathway-level targeting strategy that is directly relevant to melanoma and whose concept is transferable to other cancers.