Comprehensive analysis of cancer genomes has provided important insights in the critical alterations that confer proliferation and survival advantage to the tumor, so-called driver mutations. Tumors harboring these genetic changes frequently exhibit striking sensitivities to inhibition of these oncogenic driver pathways, a principle referred to as oncogene addiction. Substantial progress has been made in the development of drugs that specifically target components of the pathways that are associated with these driver mutations. This has enabled the first steps in a shift from the use of cytotoxic drugs to highly selective targeted therapeutic agents for the treatment of cancer. Unfortunately, despite the expanding development of targeted anti-cancer strategies, treatment failure due to primary or acquired resistance is still an almost inevitable outcome in most advanced human cancers. Understanding drug resistance mechanisms will help design more efficient combination treatment strategies that help block resistance mechanisms before they become clinically manifest. In this review, we discuss how RNA interference functional genetic screens can be used to identify clinically relevant mechanisms of drug resistance and how this technology can be used to develop effective combination therapies.
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