Programmed evolution: Using asexual gene drives to sculpt tumor populations and combat genetic diversity

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• Justin Pritchard, Penn State College of Engineering
• Monday 29 April 2024, 12:30-13:30
• CRUK CI Lecture Theatre.

If you have a question about this talk, please contact Kate Davenport.

Tumor heterogeneity is profound, and it provides a remarkable substrate for evolution. Despite this tremendous heterogeneity, single drugs targeting single oncogenic driver mutations can create deep responses in patients. However, these responses are ultimately lost due to the evolution of drug resistance. What if a tumor’s astonishing capacity for evolution could be hijacked to our benefit? Towards this idea, we recently developed a selection gene drive system that is stably introduced into cancer cells and is composed of two genes, or switches, that couple an inducible fitness advantage to a shared fitness cost. Using stochastic models of evolutionary dynamics, we developed design criteria for effective selection gene drives. We then build prototypes that harness the selective pressure of multiple approved tyrosine kinase inhibitors by inducing drug resistance and then deploying a second “trojan horse” switch to collapse a heterogeneous population using mechanisms as diverse as prodrug catalysis and immune activity induction. Using saturation mutagenesis and genome-wide sgRNA libraries, we show that the dual-switch selection gene drives constitute a simple motif for evolutionary control that can eradicate diverse forms of genetic resistance in vitro. Finally, using models to guide treatment scheduling, we demonstrate that carefully controlled switch engagement starting in a small fraction of cells (10% or less) can eradicate tumors in vivo.

This talk is part of the Seminars on Quantitative Biology @ CRUK Cambridge Institute series.

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