Harnessing Tumor Evolution to Circumvent Resistance

High-throughput sequencing can be used to measure changes in tumor composition across space and time. Specifically, comparisons of pre- and post-treatment samples can reveal the underlying clonal dynamics and resistance mechanisms. Here, we discuss evidence for distinct modes of tumor evolution and their implications for therapeutic strategies. In addition, we consider the utility of spatial tissue sampling schemes, single-cell analysis, and circulating tumor DNA to track tumor evolution and the emergence of resistance, as well as approaches that seek to forestall resistance by targeting tumor evolution. Ultimately, characterization of the (epi)genomic, transcriptomic, and phenotypic changes that occur during tumor progression coupled with computational and mathematical modeling of tumor evolutionary dynamics may inform personalized treatment strategies. Cancer is a multiscale system and a detailed understanding of the dynamics of tumor progression and the development of resistance necessitate spatial and longitudinal genotypic and phenotypic measurements, coupled with computational modeling. Multiregion sequencing provides important spatial information related to subclone architecture and tumor growth dynamics. While longitudinal sampling via repeat tissue biopsies is generally intractable, ctDNA can be assayed in a noninvasive fashion and provides information about overall tumor burden, minimal residual disease, and clonal dynamics during therapy. Although single-agent targeted therapies commonly result in resistance, other regimens that contend with and capitalize on tumor evolution (such as adaptive therapy, immunotherapy, and combination therapy) have the potential to forestall it.