Why Does Cancer Treatment Sometimes Stop Working?
Cancer treatment can stop working when some cancer cells survive it and keep growing. This is called drug resistance. It can be present from the start or develop during treatment, as cancer cells change the drug's target, push drugs out, repair damage or switch to a new growth signal. This guide explains how each of these happens and what doctors do about it, in plain language.
By Chris Morais, MSc, MPhil, PhD
Published
A cancer treatment stops working when the cancer cells it targets find a way to survive it. A few cells may be hard to kill from the start, and others change during treatment. Once the sensitive cells die, the survivors multiply into a tumor that no longer responds, so doctors switch to or combine other treatments.
- What Is Cancer Drug Resistance?
- What Is the Difference Between Primary and Acquired Resistance?
- How Does Treatment Select Resistant Cancer Cells?
- How Do Cancer Cells Change or Lose a Drug's Target?
- How Do Cancer Cells Keep Drugs Out?
- How Do Cancer Cells Repair Treatment Damage?
- How Do Cancer Cells Find Another Way to Grow?
- Why Can Immunotherapy Stop Working?
- How Do Doctors Try to Prevent or Overcome Resistance?
- Frequently Asked Questions
What Is Cancer Drug Resistance?
Cancer drug resistance is when cancer cells are no longer killed or held back by a treatment that is meant to stop them[1].
Most cancer medicines work by reaching one particular part of the cancer cell, called the drug's target. The drug then either damages the cell or blocks a signal the cell needs to grow. To learn more about how drugs find and act on their targets, see How Do Medicines Work in the Body? Resistance happens when something about the cancer cell stops this from working.
Resistance is a change in the cancer cells, not in the person. It does not mean the person's body has "got used to" the medicine. It means the cancer cells that are left have features that let them survive it.
Resistance can affect every main type of drug treatment for cancer, including chemotherapy, targeted therapy, hormone therapy and immunotherapy[1],[2],[3]. It may affect one drug only, or many drugs at once. When cancer cells become resistant to several drugs that work in quite different ways, this is called multidrug resistance[1].
Cancer cells can resist treatment in several main ways, each explained later in this article[1]. The table below gives an overview.
| Way cancer cells resist | What happens | Treatments it often affects |
|---|---|---|
| Changing or losing the target | The drug can no longer attach to, or block, the part of the cell it was made for | Targeted therapy, hormone therapy, some chemotherapy |
| Keeping drugs out | Pumps push the drug out, or the cell breaks the drug down | Many chemotherapy drugs |
| Repairing damage | The cell fixes DNA damage, or blocks its own self-destruct program | Chemotherapy and radiation therapy |
| Finding another way to grow | The cell switches on a different growth signal | Targeted therapy |
| Escaping the immune system | The cell hides from, or switches off, immune cells | Immunotherapy |
What Is the Difference Between Primary and Acquired Resistance?
Primary (intrinsic) resistance means a cancer does not respond to a treatment from the very start, while acquired resistance means the cancer responds at first and then stops responding later[2],[3].
Primary (intrinsic) resistance. Here, the features that protect the cancer are already in place before treatment begins[2]. For example, the cancer may not carry the target that a targeted drug was designed to block, or it may already have a gene change that makes the drug useless against it. With primary resistance, the tumor does not shrink, or it keeps growing, even though treatment has started.
Acquired resistance. Here, the treatment works at first. The tumor shrinks or stops growing, sometimes for months or years. Then, while treatment is still going, the cancer starts to grow again[3]. Acquired resistance is the usual answer to the question "Why did my treatment work at first and then stop?"
The same cancer can show both types. Some of its cells may be resistant from the start, while others become resistant later.
How Does Treatment Select Resistant Cancer Cells?
Treatment selects resistant cancer cells by killing the cells that are sensitive to it, which leaves the harder-to-kill cells behind with space and nutrients to multiply[1],[2].
A tumor is not made of identical cells. Different cells in the same tumor carry different gene changes and behave in different ways. This is explained in Why Are Cancer Cells Within the Same Tumor Different?
When treatment starts, the following can happen:
- The drug kills the cancer cells that are sensitive to it.
- The tumor shrinks, and scans may show a good response.
- A small number of cells that the drug cannot kill well survive. Scans cannot see these few cells.
- The surviving cells keep dividing. Their daughter cells inherit the same protection.
- Over time, the tumor grows back, now made mostly of resistant cells[1],[2].
This is natural selection at work inside the body. The drug does not teach cancer cells how to resist. Instead, it removes the cells that cannot resist, so the ones that can are left to take over.
The area around the cancer cells can also help some of them survive. This area, called the tumor microenvironment, includes blood vessels, connective tissue cells and immune cells. Parts of a tumor that are low in oxygen can be harder to treat. Some normal cells in and around the tumor, such as certain connective tissue cells and immune cells, can also release signals that help cancer cells survive treatment[2].
Were Resistant Cells There Before Treatment Started?
Often, yes. Some resistant cells may already be present in a tumor before treatment begins, although in other cases resistance develops during treatment[1],[4].
Cancer cells keep picking up new gene changes as they divide (see How Do Genetic Changes Turn a Normal Cell into Cancer?). A tumor with millions of cells can therefore contain a few cells that, by chance, carry a change that protects them against a drug they have never met. Before treatment, these cells have no special advantage, so they stay rare. Once treatment starts, they are the ones that survive[1].
Other cells survive in a different way. When the drug arrives, some cancer cells slow down and enter a resting state. Scientists call these cells drug-tolerant persister cells. Their protection usually does not come from a new mutation. It comes from changes in which of their genes are switched on or off, and these cells can become sensitive to the drug again once it is removed[4]. However, if the drug pressure goes on for a long time, some persister cells can gain lasting gene changes that make them truly resistant[4]. Scientists are still working out whether persister cells already exist before treatment or are created by it. The evidence so far supports both ideas[4].
A related problem is that some cancer cells can stay in a resting, non-dividing state for a long time. Many chemotherapy drugs work best on cells that are dividing, so resting cells can survive treatment[4]. In some people, such cells may start growing again months or even years later.
How Do Cancer Cells Change or Lose a Drug's Target?
Cancer cells change or lose a drug's target by gaining a new gene change in the target, by making much more of the target, or by no longer depending on it[1],[2],[5].
Many modern cancer drugs, called targeted drugs, are designed to fit closely onto one particular protein that the cancer needs, usually a faulty growth protein. If that protein changes, the drug may no longer work[5]. This can happen in three main ways:
- A new change in the target. A small change in the target protein can alter its shape just enough that the drug cannot attach, while the protein still does its job for the cancer[1],[2]. For example, some lung cancers are driven by a faulty growth protein called EGFR. Studies have shown that about half of these lung cancers that become resistant to the early EGFR-blocking medicines have a second change in EGFR, called T790M[1]. A similar thing happens in a type of leukemia treated with medicines that block a faulty protein called BCR-ABL[1],[2].
- Much more of the target. A cancer cell can make extra copies of the gene for the target. It then produces so much target protein that the usual dose of the drug cannot block it all[1],[2]. For example, prostate cancer cells can make far more of the hormone receptor that hormone therapy is meant to block, or a shortened form of the receptor that the drug cannot switch off[1],[2].
- Losing the need for the target. If a cancer cell stops depending on the target, blocking it no longer harms the cell. This often happens when the cell switches to another growth signal, as explained later in this article.
Chemotherapy drugs can also lose their targets. For example, some chemotherapy drugs work by blocking an enzyme called topoisomerase II, which cells use to untangle their DNA when they divide. Changes in this enzyme can make these drugs less effective[1].
How Do Cancer Cells Keep Drugs Out?
Cancer cells keep drugs out mainly by pumping them back out of the cell before they can cause harm, and sometimes by breaking the drug down or failing to activate it[1].
A drug only works if enough of it builds up inside the cancer cell. Cancer cells can lower the amount of drug inside them in several ways[1]:
- Pumping the drug out. Proteins in the cell's outer layer push the drug back out. This is one of the most studied causes of resistance, and it is explained in the next section[1].
- Breaking the drug down. Cells can attach other chemicals to a drug that make it harmless and easier to remove. One of these is glutathione, a small molecule cells normally use to protect themselves from harmful substances[1].
- Failing to activate the drug. Some chemotherapy drugs are given in an inactive form and must be switched on by the cell's own enzymes. If cancer cells make less of these enzymes, the drug stays inactive[1].
Drugs also need to reach the cancer cells in the first place. Tumor blood vessels are often messy and leaky, so some parts of a tumor receive less of the drug than others (see Why Do Tumors Need New Blood Vessels? Angiogenesis Explained).
What Are Drug Efflux Pumps?
Drug efflux pumps are proteins in the outer layer of a cell that push unwanted chemicals, including many cancer drugs, back out of the cell[1].
"Efflux" simply means flowing out. Many normal cells use these pumps to protect themselves from harmful substances. They belong to a large family of proteins called ABC transporters. The best known is P-glycoprotein, which is made from a gene called MDR1. MDR stands for multidrug resistance. Two other important pumps are called MRP1 and BCRP[1].
Efflux pumps are a major cause of multidrug resistance because one pump can push out many different drugs. A cancer cell that makes a lot of one pump can therefore become resistant to several chemotherapy drugs at once[1].
Some cancers have high levels of these pumps before treatment begins. In others, the cancer cells make more of the pumps after being exposed to drugs[1]. Medicines that block these pumps have been tested, but none has yet become a standard part of cancer treatment.
How Do Cancer Cells Repair Treatment Damage?
Cancer cells repair treatment damage by using, and sometimes boosting, the cell's own DNA repair systems to fix the harm caused by chemotherapy before it can kill the cell[1].
Many chemotherapy drugs, such as platinum drugs like cisplatin, work by damaging DNA. Radiation therapy also works mainly by damaging DNA. A cell with too much DNA damage cannot divide properly and usually dies.
All cells have repair systems that find and fix damaged DNA. Cancer cells can use these systems to undo the damage that treatment causes[1]. For example:
- Platinum drugs create links in DNA that block it from being copied. Cancer cells can resist these drugs by repairing this damage with repair systems that cut out the damaged section or rebuild the broken DNA using an undamaged copy as a guide[1].
- Some chemotherapy drugs add small chemical groups to DNA. A repair protein called MGMT can remove these groups, which protects the cancer cell[1].
Cancer cells can also survive damage without fully repairing it. Normally, a cell with serious damage destroys itself in a tidy, controlled way, called apoptosis. Cancer cells can block this self-destruct program, for example by making extra amounts of survival proteins such as BCL-2[1]. The cell then stays alive even though treatment has harmed it.
DNA repair can also work in the other direction. Some cancers have faulty repair systems. This can make them more sensitive to certain drugs, such as PARP inhibitors, which block a backup repair route that these cancers rely on[2].
How Do Cancer Cells Find Another Way to Grow?
Cancer cells find another way to grow by switching on a different growth signal that does the same job as the one the drug has blocked[2],[5].
Cells grow and divide in response to chains of signals passed from one protein to the next. In many cancers, one faulty protein keeps a growth signal switched on all the time. This is explained in Why Do Cancer Cells Keep Growing? Targeted drugs work by blocking that faulty protein.
Cancer cells can get around this block in several ways[2]:
- Using a different signal. The cancer cell switches on a second growth protein that feeds into the same signal chain further along. For example, some lung cancers that become resistant to EGFR-blocking medicines make extra copies of a gene called MET. MET then sends the growth signal that EGFR can no longer send[2].
- Restarting the blocked signal. Signal chains have built-in brakes that slow them down when they are very active. When a drug blocks the chain, these brakes can ease off. This can let the signal start up again from another point in the chain[2].
The result is that the drug still attaches to its target, but the cancer cell no longer needs that target to grow[5]. This is one reason targeted drugs are often given together with other targeted drugs, or with other treatments[5].
Why Can Immunotherapy Stop Working?
Immunotherapy can stop working when cancer cells find new ways to hide from, or switch off, the immune cells that the treatment has released[3].
The most widely used immunotherapy drugs, called immune checkpoint inhibitors, release the brakes on T cells so they can attack the cancer. How these brakes work, and how cancer cells use them, is explained in How Do Cancer Cells Hide from the Immune System?
Primary resistance to immunotherapy is often seen in tumors where few T cells are present to begin with. Releasing the brakes does little if there are no immune cells to release[3].
Acquired resistance can happen in several ways[3]:
- Hiding from T cells. Cancer cells can lose a protein called beta-2 microglobulin, which they need to display protein pieces on their surface. Without it, T cells cannot recognize them.
- Ignoring immune signals. T cells release a signal called interferon-gamma that helps the attack. Cancer cells can lose the proteins (JAK1 or JAK2) they need to respond to this signal.
- Losing the abnormal proteins. Cancer cells that no longer make the abnormal proteins T cells were targeting can survive and multiply.
- Using other brakes. Tumors can switch on other immune brakes, such as TIM-3 and LAG-3, which the treatment does not block.
- Recruiting immune cells that calm the attack. Tumors can attract immune cells whose normal job is to hold back the immune response.
Studies have shown that, among people whose cancer first responds to checkpoint inhibitors, about 4 in 10 on average later see the cancer grow again, though this differs widely between cancer types[3]. For other people, the response can last for years[3].
How Do Doctors Try to Prevent or Overcome Resistance?
Doctors try to prevent or overcome resistance by matching treatment to the cancer's features, combining treatments that work in different ways, watching for regrowth and switching treatment when resistance appears[2],[5].
The main approaches include:
- Testing the cancer first. Testing a tumor sample for the targets a drug needs is called biomarker testing. It helps doctors avoid drugs that a cancer is unlikely to respond to from the start[5].
- Combining treatments. Using two or more treatments that work in different ways means a cancer cell would need to resist all of them at once, which is much less likely[2],[5]. This is why chemotherapy drugs are often given in combination, and why targeted drugs are sometimes combined with other targeted drugs, chemotherapy or radiation[5].
- Using newer drugs designed for resistance. When scientists learn which change causes resistance, they can design new drugs that still work against it. Some of these newer drugs are made to work against target changes such as T790M in lung cancer[2].
- Testing the cancer again. Testing a cancer more than once over time can show how resistance develops[2]. When a cancer grows during treatment, a new biopsy or, for some cancers, a blood test can show which resistance change has appeared, and the result can guide the choice of the next treatment.
- New strategies under study. Scientists are testing approaches such as adaptive therapy, in which doses are adjusted or paused so that drug-sensitive cells remain and compete with resistant cells for space and nutrients[2]. This approach is still being studied and is not yet standard care.
Resistance does not mean that cancer treatment is not worth having. Many treatments control cancer for months or years, and many cancers are cured before resistance ever becomes a problem. When one treatment stops working, there are often other options. Stopping or skipping treatment does not prevent resistance. Anyone having cancer treatment should keep taking it as prescribed and talk to their care team before making any change.
Frequently Asked Questions
Why does chemo stop working after it worked at first? Chemotherapy first kills the cancer cells that are most sensitive to it, which is why the tumor shrinks. A small number of cells that are harder to kill, or that are resting and not dividing, can survive. These cells then multiply, and the cancer that grows back is made mostly of cells that the same chemotherapy cannot kill as well[1],[4].
Can cancer become sensitive to treatment again? Sometimes. When resistance comes from temporary changes, such as in drug-tolerant persister cells, laboratory studies show that the cells can become sensitive again after the drug is stopped[4]. In some situations, doctors may try an earlier treatment again after a break. Resistance caused by lasting gene changes usually does not reverse, so a different treatment is often needed.
How do doctors know a cancer treatment has stopped working? Doctors usually find out through regular scans that show a tumor growing or new tumors appearing. New or worsening symptoms can also be a sign. For some cancers, blood tests that measure substances released by the cancer, called tumor markers, can rise before changes show on a scan.
Is cancer drug resistance the same as antibiotic resistance? They follow similar principles. In both, a treatment kills the sensitive cells and leaves resistant ones to multiply, and both can involve pumps that push drugs out. The main difference is that cancer drug resistance develops in a person's own cancer cells and cannot spread to other people, while resistant bacteria can pass between people. See How Do Bacteria Become Resistant to Antibiotics?
Does every cancer become resistant to treatment? No. Many cancers are removed by surgery, or cured by treatment, before resistance has a chance to develop. Resistance is a bigger problem in cancers that have spread and need treatment over a long time, because a larger number of cancer cells and a longer time on treatment give resistant cells more chances to appear and take over.
Morais C. Why Does Cancer Treatment Sometimes Stop Working? [Internet]. BiologyWithin.com; 2026 Oct 16. Available from: https://www.biologywithin.com/2026/10/why-cancer-treatment-stops-working.html
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- National Cancer Institute. Targeted therapy to treat cancer. Bethesda (MD): National Cancer Institute.
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