In one aspect, the invention is directed to a method of characterizing a mechanism of action of a combination of agents. The method comprises contacting a plurality of populations of cells with a combination of agents to be assessed, wherein each population of cells have one gene of interest targeted by a small hairpin RNA (shRNA) and wherein the gene of interest regulates cell death and a plurality of genes that regulate cell death are targeted in the plurality of populations of cells. A responsiveness of each population of cells to the combination of agents is determined, thereby obtaining an shRNA signature of the combination of agents so as to identify one or more genes that mediate a response to the combination of agents, thereby characterizing the mechanism of action of the combination of agents. In another aspect, the invention is directed to a method of determining whether a patient population treated with a first agent would benefit from a treatment using the first agent in combination with one or more additional agents. In yet another aspect, the invention is directed to method of determining whether a formulation of one or more agents maintains a mechanism of action of the one or more agents when unformulated.