06 March 2024

Check Up #23 - Why does cancer become resistant to drugs?

Cancer resistance to drug treatments is a very serious problem: it is one of the main causes of treatment failure. Even though the treatment may still be able to kill part of the cancer cells, the resistant ones will survive and thrive. But why does a drug that has proven successful in reducing or controlling a patient’s cancerous tumour for a while suddenly stop working? Because cancer cells unfortunately have various “tricks up their sleeve”, so to speak.

Check Up #23 - Why does cancer become resistant to drugs?

Cancers become resistant to chemotherapy in two major ways. They either have preexisting resistance to a type of drug or they can develop resistance through mutations.

Here are some of the main reasons for cancer drug resistance to arise. 

First of all, as just mentioned, drug resistance may be already present before the treatment even starts. For some reason, a certain population of tumour cells is not sensitive to the treatment in question. This is possible because tumours are not homogeneous entities, which means that they contain multiple cell strains with different molecular and genetic makeups, some of which confer cells an a priori resistance to certain drugs and allow them to survive the treatment. 

Cancer drug resistance can also develop in response to the treatment itself. This can take weeks or even years to occur and can be due, in particular, to mutations of the drug’s target molecule on the cancer cells, which change the target’s configuration and diminish or abolish the drug’s ability to strongly bind to it and have its intended therapeutic effect.

Yet another cause of drug resistance are so-called epigenetic changes to the cancer cells’ DNA in response to a given drug. These are not genetic mutations, but rather changes in the levels of gene expression, and they can enhance the cancer cells’ ability to pump the drug out of itself, thus once again decreasing its therapeutic effects. This happens, in particular, when cancer cells respond to the treatment by increasing the production of certain proteins that normally pump out toxic agents from healthy cells. A process which cancer cells are able to subvert.

Many anticancer drugs work by damaging the cancer cell's genes to the point that the cell “commits suicide” in a process called apoptosis. But instead of blocking or impairing the action of the drug itself, some cancer cells can “learn” to repair their own DNA, managing to defeat this cell-death mechanism.

Finally (but this list is not exhaustive), drug resistance can be due to conditions reigning in the area around the tumour, or “microenvironment”. These conditions, which may change during the treatment, can protect the tumour against attacks by the immune system.

To try to overcome drug resistance, several chemotherapies may be administered in combination. Experts are also searching for ways to reverse epigenetic changes, block the production of drug-expelling cellular substances, alter the tumour environment or stimulate the patient’s own immune system. 



By Ana Gerschenfeld, Health & Science Writer of the Champalimaud Foundation.

Reviewed by: Professor António Parreira, Director of the Champalimaud Clinical Centre.
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