The development of more targeted anticancer drugs is ongoing. It has been driven by breakthroughs in our understanding of the molecular mechanisms that lead to out-of-control division of cancer cells. This has also brought deeper insight into how cancer cells become resistant to treatment.
Resistance of cancer cells to drugs is a question of the survival of the fittest – a Darwinistic mechanism similar to the development of antibiotic resistance in bacteria. If a particular cancer cell happens to have a property that enables it to avoid being killed by the drug then it will be selected for and continue to multiply. This natural law normally protects the organism, but in the case of cancer treatment can be fatal.
There are many mechanisms of resistance, including:
However, perhaps the most studied form of resistance involves drug metabolism. This includes uptake, efflux or ejection of the drug from the cell, and detoxification or breakdown by thebody.
The cellular mechanisms for uptake and ejection of drugs are particularly important and can lead to multidrug resistance. This is where the affected cells acquire the ability to resist the effect of many drugs.
Dr. Michael Gottesman, now at the National Cancer Institute in the USA, and his colleagues discovered an example of this: P-glycoprotein (P-gp), a cell-surface protein that pumps drugs out of the cell. It was a groundbreaking discovery, which led to a massive research effort to understand the extent of drug efflux mechanisms.
Several pumps, or ABC transporters, have since been discovered. These are capable of forcing out all known anticancer agents and can result in multi-drug resistance (MDR). Like so many other mechanisms that defeat treatment, these efflux pumps are the evolutionary result of the body’s fight for survival – in this case the need to pump out foreign and potentially toxic substances, or xenobiotics, from the cell.
Knowledge is power, and in the final part of this series we will look at a few examples of how resistance to anticancer drugs is being overcome, and take a glimpse into the future of cancer treatment.
Next in this three-part series: Let’s make this personal