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It is widely known that secondary resistance inevitably leads to treatment failure through Darwinian evolution. Therefore, quantifying the clonal evolution using experimental model systems can hold a great promise in designing evolutionarily informed therapies, and thus, in predicting drug response. In this talk, I present our recently developed strategy that contributed to the understanding of collateral drug sensitivity with its direct link to clonal evolution to overcome the drug resistance in non-small cell lung cancer cell line model system. Additionally, I also present a similar approach that has been developed to delineate chemotherapy induced clonal alterations in colorectal cancer cell line model systems. More specifically, high-complexity cellular barcoding allowed us the identification of the resistance that was ultimately driven by the presence and emergence of multiple pre-existing and de novo resistant clones, respectively. Overall, our work highlights evolutionary tradeoffs and provides an opportunity to exploit the tumour vulnerability.