FIGURE 4.

The rheostat of repeat element de-regulation and restriction in tumor evolution and drug resistance. The evolution of cancer and drug resistance may be described as a battle between factors that decrease and promote tumor fitness and immunogenicity. Upon drug-induced stress or DNA hypomethylation, de-repression of repeat elements leads to loss of cancer cell fitness and activation of innate and adaptive tumor immunity, in part driven by viral sensing and DDR mechanisms (left). Compensatory mechanisms, such as epi-transcriptome regulation, DNA repair, DNA/RNA editing, and R-loop resolution factors can all contribute to the establishment of a balance that promotes tumor development and the evolution of drug resistance (as indicated by the changes in circle size in the right part of the figure). Future studies will determine whether new tumor therapy strategies aimed at disrupting this balance can result in more curative outcomes.