Exploiting evolutionary steering to induce collateral drug sensitivity in cancer

• DOI: 10.1038/s41467-020-15596-z
• Publication Date: 2020-04-21T10:04:37Z
• Authors: Ahmet Acar; Daniel Nichol; Javier Fernandez-...; George D. Cresswell; Iros Barozzi; Sung Pil Hong; Nicholas Trahearn; Inmaculada Spiteri; Mark Stubbs; Rosemary Burke; Adam Stewart; Giulio Caravagna; Benjamin Werner; Georgios Vlachogi...; Carlo C. Maley; Luca Magnani; Nicola Valeri; Udai Banerji; Andrea Sottoriva
• Keywords: Lung Neoplasms; EGFR BLOCKADE; TUMOR HETEROGENEITY; Stochastic Processe; Drug Resistance; Pyridone; Antineoplastic Agent; TARGETED THERAPY; Theoretical; Models; Pyrimidinone; 0303 health sciences; Q; Gefitinib; CLONAL EVOLUTION; 3. Good health; Multidisciplinary Sciences; Science & Technology - Other Topics; Molecular Medicine; Human; 570; Genotype; Evolution; Pyridones; CELL LUNG-CANCER; Science; COMPETITION; Antineoplastic Agents; Pyrimidinones; Antineoplastic Agents; Clonal Evolution; Computational Biology; Computer Simulation; Gefitinib; Genotype; Humans; Lung Neoplasms; Models, Theoretical; Molecular Medicine; Pyridones; Pyrimidinones; Stochastic Processes; Drug Resistance, Neoplasm; Evolution, Molecular; Article; Clonal Evolution; Evolution, Molecular; 03 medical and health sciences; Humans; Computer Simulation; Stochastic Processes; Science & Technology; MUTATIONS; Molecular; Computational Biology; Models, Theoretical; 620; Lung Neoplasm; COPY NUMBER; Drug Resistance, Neoplasm; Neoplasm; INHIBITORS; ACQUIRED-RESISTANCE

AbstractDrug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using ‘evolutionary steering’ to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108–109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance.