Finally, we see that some drugs appear to target sensitivities in the population of drug-naive cells that are “primed” to become resistant, and these sensitivities can be lost as the cells become fully resistant. (9/10)

Through a collaboration with Stephanie Huang and Robert Gruener at the University of Minnesota, we showed that their independent drug action-based model, IDACombo, could accurately predict combination efficacy. (8/10)

When we tested this combination in vitro, we saw that it was indeed more effective than either drug individually! This result is an example of population-based synergy, where two drugs target distinct populations, rather than both drugs acting on the same population. (7/10)

We wondered whether there were combinations of drugs targeting distinct subsets of the resistant clones. To test this, we expanded our pool of clones and identified a number of potential combinations, including the example shown. (6/10)

To test this, we generated clonal, resistant cell lines (dubbed resistant clones) from individual resistant colonies and screened them with a pan-cancer drug library. We found that resistant clones indeed had distinct drug sensitivities! (5/10)

If so, there may not actually be one “silver bullet” that could kill all the cells. Instead, drugs may target distinct subpopulations of resistant cells. In a bulk assay, such drugs might appear to have similar partial effects, but could actually be quite effective in combination. (4/10)