Treatment Resistant 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 topoisomerase II such that it can no longer bind to the drug, making the drug ineffective.

The third drug resistance strategy is an increase in drug efflux from cancer cells. For example, the gene MDR1 encodes for an ATP-binding cassette transporter, or ABC transporter, that can pump lipophilic drugs out of the cell. Resistant cancer cells often overexpress the transporter, reducing the drug’s intracellular concentration.

The Mdr1 transporters can efflux a broad range of drugs used in chemotherapy and result in multidrug resistance in the cancer cells.

The fourth resistance strategy is to elevate the DNA damage response. Some alkylating drugs methylate the guanine nucleotide into O6-methylguanine, causing mismatch mutations in the tumor cells.

Resistant tumor cells can overexpress an enzyme called O6-methylguanine methyltransferase, or MGMT, which converts the modified base back to guanine before the mutations are passed onto the next generation, thus negating the drug action.