Synthetic lethality and chemoresistance in cancer

Despite great strides in the development of anti-cancer strategies over the last 50 years, treatment regimens continue to cause significant toxicity and fail to fully eradicate disease. Enhancing the current state of therapy will require: (1) the expansion of available tumor selective and therapeutically tractable molecular targets, (2) the development of methods to provide a rational approach to identifying effective combinatorial drug cocktails, and (3) molecular markers that can accurately predict sensitive patient populations. To this end, efforts that reveal the molecular architecture supporting tumorigenic phenotypes are essential. RNA interference (RNAi)-mediated loss of function screens have emerged as a method for wholesale identification of tumor-specific dependencies that modulate chemo responsiveness. Here, we provide a broad overview of how genome-scale RNAi screening is being implemented. Cancer chemotherapy Cytotoxic chemotherapy Goodman and Gilman's 1946 discovery that lymphosarcomas respond to nitrogen mustard demonstrated that tumor cells may have an enhanced sensitivity to chemical poisons as compared to their normal counterparts. This finding revolutionized cancer treatment as it indicated that in addition to radiation and surgery, the only available modalities at the time, drugs could also be administered to reduce tumor burden (Goodman et al. 1946). Following on these initial observations, over the ensuing 50 years, an arsenal of cytotoxic agents were developed to treat a range of cancer types (Chabner and Roberts 2005, Strebhardt and Ullrich 2008). The majority of these agents, as with the nitrogen mustard, share a common characteristic: they induce genomic damage. For example, agents such as cisplatin cause inter-and intrastrand DNA cross links. This DNA damage can lead to the inhibition of cell division by activating an arrest in the cell cycle to allow for DNA repair through the nucleotide excision repair (NER) pathway. This pathway is coupled to apoptotic programs that are activated if overwhelming damage is detected (Plunkett et al. 1995, Siddik 2003, Wang and Lippard 2005).