FIGURE 1.

Innate and acquired drug resistance in cancer. Tumors can display innate resistance to therapy (red arrow), the causes and origins of which are not completely understood. Tumors can also develop acquired therapy resistance (blue arrows). Upon exposure to therapy and response, a fraction of tumor cells survive the initial lethal drug exposure–drug-tolerant persister (DTPs) cells. This dormant state, which can be reversible, contributes to therapy relapse or the establishment of drug-tolerant expanded persister cells (DTEPs) that harbor many genetic and epigenetic changes developed in order to adapt to the drug exposure. It should be noted that rare pre-existing resistance mutations have also been found in human tumors. The DTEP state can, following a “drug holiday,” return to a drug-responsive tumor state (black, dotted arrow), a phenomenon reported in tissue culture and in patients. Many mutational, non-reversible, resistance mechanisms have also been described in tumors from patients that have relapsed on therapy.