In previous research, we have found that co-expressed microRNAs exert profound impacts on cell phenotype through their synergistic activities (Cursons et al, Cell Systems, 2018). Building upon this fundamental discovery, here we utilise combinations of both optimised siRNAs, and a novel class of siRNA:miRNA hybrid we have developed, to cross-target all 10 core kinases within the RAS/RAF/MAPK pathway which is commonly dysregulated in cancer where it drives cancer survival and proliferation. We find that by combining therapeutic small RNAs, we can selectively reduce the viability of RAS-dependent cancer cells (derived from melanoma, liver cancer and breast cancer) at greatly reduced dosage than is required with single siRNAs, and that the same combinatorial RNAs are able to kill cancer cells irrespective of the specific hyperactivating mutation in the RAS pathway. Importantly, cells not dependent upon constitutive RAS signalling are unaffected by RNA treatment. The cross-targeting RNA cocktail is also still effective, even after cells have acquired resistance to a standard front-line anti-RAS therapy (vemurafenib). Lastly, we present transcriptomic analyses to demonstrate the reduced RNA dosage is associated with greater on-target and lower off-target effects than is seen with traditional single-target approaches which necessitate the use of more RNA. Collectively, this work demonstrates the advantages of a combinatorial RNA approach to therapy as a means to reduce dosage, decrease off-target toxicity and provide broad-effectiveness through pathway-level targeting. This cross-targeting mechanism is commonly used in biological systems, though the vast majority of microRNA research fails to model this mode of action in favour of single RNA studies that are heavily reliant upon over-expression and that fail to model the complexities of small RNA synergism which is essential when expressed at endogenous levels.