CancerQuest | Cancer Drug Resistance: Gene Amplification

As described in the previous sections, cancer drugs work by a variety of mechanisms. How is it that cancer cells can become resistant to these different drugs? Listed below are some of the common ways in which cancer cells avoid cell death in the face of chemotherapy and other treatments.

Increased expression of target proteins: Some cancer drugs, such as methotrexate, are designed to inhibit particular enzymes in key pathways controlling cell growth and division. Increased expression (transcription) of the gene that controls levels of the target molecule can cause a large increase in the amount of that target molecule in the cell. Since the drug concentration in the cell is limited by the dosages that can be given, the increased numbers of target molecules means that many of the targets do not get affected by the drug. There are just too many for the number of drug molecules present. In the amination below you can see that in the first situation, all of the 'target' molecules (green) are bound by the drug (red). In the second situation, there are too many target molecules present. In a cell, this would mean that the drugs effectiveness would decrease, perhaps to a point where it no longer slowed cell growth.⁽¹⁾

One mechanism by which the expression of the target genes can become elevated is through the process of gene amplification. This process involves the selective replication of a region of a chromosome. The process can be repeated many times, making many copies of that particular region. The gene amplification event is diagrammed schematically below. The normal replication process is depicted on the left and the amplification of a portion of the chromosome is shown on the right

The genes within the amplified portion of the chromosome can each be transcribed, leading to the production of a large amount of the proteins encoded by those genes.⁽¹⁾ ⁽²⁾