Treatment Resistent Cancers

Genetic instability allows cancer cells to acquire resistance to therapeutic drugs at a rapid rate.

For instance, while the initial drug treatment can eliminate most of the tumor cells, a small fraction of resistant mutant cells, called persisters, may tolerate the drug treatment and divide to form another tumor. All the cells of this new tumor are now resistant to the initial drug, resulting in therapeutic failure.

Cancer cells use several strategies to develop resistance to treatment.

The first is inhibition of drug activation. For example, the drug Cytosine arabinoside used to treat acute myelogenous leukemia must be activated intracellularly by multiple phosphorylation events. Cancer cells with mutations in this activation pathway can inhibit the activation of Cytosine arabinoside, leading to the drug resistance. 

The second strategy is drug target modification. Consider the enzyme topoisomerase  II, which reduces DNA supercoiling and enables smoother DNA replication in cells. Certain anticancer drugs target and inhibit the topoisomerase activity in order to stall DNA replication in rapidly dividing cancer cells.

However, resistant cancer cells can mutate the enzyme topoisomera