Busch, G. T.; Boe, R. H.; Li, J.; Gruener, R. F.; Arnett, M. J.; Ravindran, P. T.; Herlyn, M.; Huang, R. S.; Raj, A.

Resistance to targeted therapies is a significant clinical problem, but eliminating resistant cancer cells has proven difficult. One potential reason for this difficulty is heterogeneity in the resistant population: even genetically homogeneous cancer cell populations can give rise to a variety of resistant subtypes, each potentially with their own specific second-line drug vulnerabilities. Using high-throughput drug screening of genetically-identical resistant clones with varying transcriptomes and morphologies, we show that each clone had a distinct drug sensitivity profile. These results admitted the possibility that there are drugs that are effective against only subsets of therapy resistant populations but in combination eliminate a large proportion of the resistant population. Using the individual clone sensitivity profiles, we prospectively identified combinations that were highly effective at eliminating most of the resistant population. Our results demonstrate the effectiveness of \'\'subpopulation-directed synergy\'\', showing that considering population heterogeneity can reveal therapeutic opportunities otherwise masked by population averages, offering new strategies to combat therapy resistance.