PMC

Individually, EGFR and KRAS mutations both confer a survival and/or reproductive benefit to lung cells, and are thus positively selected. However, if a cell contains both oncogenic mutations, there is a decline in survival and/or reproduction. Therefore, the double mutant is subject to negative selection—in this case, an epistatic effect of the possession of one mutation upon the selection imposed on the second mutation.

Each tumor is initiated by an original cell population (orange), and populations expand in size (vertical axis) over time (horizontal axis). As the tumor grows, a new subclone (blue) can be founded via a mutation that confers a more extensive cancer phenotype, and can grow alongside or supplant the original population. Targeted treatment (blue line) specifically eliminates the new population that it targets (blue), leading to a varying consequence on the tumor that depends on the extent of intra-tumor heterogeneity, which is determined by its selective effect. Tumors with a high proportion of their cells belonging to the population affected by treatment are most likely to experience the greatest reduction of tumor burden, the longest remission before recurrence, and the greatest opportunity for cure.