Overview

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or impaired apoptosis.

Origin of resistant cells

Given the heterogeneous nature of the cancer cells, a tumor can have various cancer cell subpopulations, each with distinct genetic fingerprints. Some of these cells may have pre-existing mutations or acquire new mutations that confer them drug resistance. Under therapeutic pressure, cancer cells obey the Darwinian law of evolution, and only the cells that are most adaptive and resistant to treatment survive and multiply to take over other susceptible cancer cell subpopulations.

Models for cancer resistance

Two models are put forward to explain resistance to anticancer drugs. One is the cancer stem cells (CSC) model, and another is the Environment-mediated drug resistance (EMDR) model.

Cancer stem cells or CSCs are quiescent cells with increased DNA repair efficiency, altered cell cycle parameters, or overexpression of anti-apoptotic properties or drug transporters. In this model, drug resistance is mostly caused by the intrinsic or acquired resistance of accumulating CSCs and not all cancer cells within a tumor.

In the Environment-mediated drug resistance (EMDR) model, cancer cells interact with the surrounding environment to enter a quiescent or dormant state to escape the drugs. Inside their protective zone composed of the tumor microenvironment, cancer cells undergo genetic changes until they acquire resistant phenotype. The cells can then relapse once the drug is withdrawn.

Procedure

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.