Using evolutionary-conserved mechanisms to target resistance in leukemia

Summary:

Local adaptation directs populations towards environment-specific fitness maxima through acquisition of positively-selected traits. However, rapid environmental changes can identify hidden fitness trade-offs that turn adaptation into maladaptation, resulting in evolutionary traps. Cancer, a disease prone to drug resistance, is in principle susceptible to such traps. A series of CRISPR/Cas9 knockout screens was used to profile functionally the sensitivity of acute myeloid leukemia (AML) cells treated with various targeted therapies and chemotherapies, and map the drug-dependent genetic basis of their fitness trade-offs. We identified various drug-induced antagonistic pleiotropy and collateral sensitivity mechanisms that can be leveraged to design evolutionary traps that selectively target drug resistance across diverse AML cell lines, syngeneic and PDX models of AML

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