Fig. 1.

Overcoming cancer drug resistance using a double-synthetic lethality approach. In the presence of a normal or cancer cell with 2 functional synthetic lethal genes (genes A and B), if only one of the genes is inhibited (gene B), cells remain viable. However, if this cancer cell has already a mutation on one of the genes (gene A) that impairs its function and the other gene is inhibited this results in cancer cell death. When cancer resistance appears due to for example the mutation or over-expression of an additional gene (gene C), it may be possible to overcome this resistance by designing an inhibitor that targets gene C, thereby restoring cancer cell lethality through this double-SL approach. Figure created with BioRender