Fig. 1

Models of drug resistance mechanisms following cancer targeted therapy. The EGFR-mutant model of drug resistance in lung cancer is shown here as an example. There are two recognized models of mechanisms of drug resistance known as preexisting mutations and adaptive evolution. In the preexisting mutations model, certain tumor cells growing within the parental population already have a survival advantage due to a preexisting mutation that can resist the targeting agent. Under continuous drug treatment, cells harboring the resistant mutation survive and proliferate to become the dominant clone, resulting in clinical drug resistance and tumor progression. Drug withdrawal at this point does not readily change the molecular makeup the cells. By contrast, in the adaptive evolution model, most tumor cells begin with a level playing field, with the exception of a subpopulation that may have been primed to activate prosurvival signaling pathways by an unknown regulatory or selective mechanism. While the majority of cells die under continuous drug treatment, a small subpopulation within the originally drug-sensitive cells will escape their initial dependence on the driver mutation, despite ostensibly identical genotype/genomic milieu, by adaptively altering either their transcriptome, signaling, or epigenome in a directed effort to survive against therapeutic pressure. This reprogramming process engenders the drug-escaping cells to enter into proliferative and metabolic quiescence. These adaptively resistant cells eventually acquire and accumulate mutations advantageous for further proliferative growth and the tumor progresses in fulminant resistance. In both aforementioned cases, the residual disease cells grow into a completely different tumor than the original under therapeutic pressure. However, previous work in vitro has demonstrated that early drug withdrawal can revert the adaptively resistant cells back to their parental, drug-sensitive state. This observation highlights the need for studying early adaptive resistant tumor cell populations and the mechanisms governing their shift to acquired resistance