Leveraging experimental evolution to extract predictive collateral drug response signatures in Ewings Sarcoma

Collateral sensitivity, where resistance to one drug confers sensitivity to another, could be leveraged to optimize chemotherapy for EWS. Gene expression signatures that predict collateral sensitivity states can be used to guide treatment selection in an evolution-informed manner.

To generate such biomarkers, we experimentally evolved resistance to first-line EWS chemotherapy in independent replicates of an EWS cell line, all originating from the same ancestor population. Throughout, we measured collateral responses across a panel of anticancer drugs and quantified transcriptomic changes. Collateral drug responses varied across replicate evolutionary trajectories, but convergent states of collateral sensitivity emerged across different replicates at different times.