How Does Cancer Become Resistant to Chemotherapy?

Even when treatment is successful at shrinking or stabilizing tumor growth, there’s a risk your cancer will stop responding to the drugs you’re taking. Cancer drug resistance, also known as chemotherapy resistance, can happen when cancers that used to respond to a drug or therapy suddenly start to spread or grow again.

If the cancer cells begin to resist the chemotherapy drugs and their effects, your doctor will change your treatment plan and the drugs you’re taking. You might be told that the chemotherapy failed or that your tumor is now chemorefractory, but other chemotherapy drugs or other types of treatment may still work.

Drug resistance is one of the main causes of cancer treatment failure. It can lead to recurrence or relapse of cancer or death. This article will explain what cancer drug resistance is, what causes it, and ways to avoid it. 

Types of Drug Resistance - Illustration by Michela Buttignol

Verywell / Michela Buttignol

Causes of Cancer Drug Resistance

There are two main types of drug resistance. Intrinsic drug resistance is already present before the treatment starts. Extrinsic resistance develops in response to the treatment.

There are many ways that anticancer drugs work. Treatments like chemotherapy typically require the drug to bind to a protein either inside or on the outside of the cancer cells. This binding causes a cascade of reactions inside the cell that results in the cell dying.

Changes to the target proteins that bring the drug into the cell—or any other protein along pathways involved in the drug’s effects—can impact how well the treatment works. There are many ways that the cells can change these proteins.

The following are ways are the different mechanisms through which cancer develops either intrinsic or extrinsic drug resistance.

Intrinsic Drug Resistance

Intrinsic drug resistance is characteristics of the tumor as a whole that are typically present before treatment even starts. Intrinsic drug resistance may be apparent in a shrinking tumor that then stops responding to treatment or starts to grow bigger even as treatment continues. 

Ways that cancer cells develop intrinsic drug resistance include:

Existing Cellular Differences

Cancer cells aren’t all the same. Even within one tumor, there can be multiple cancer cell strains with different molecular and genetic characteristics.

Some of these cancer cells may have mutations (changes in their genes) that give them drug resistance. Once the treatment has killed off the vulnerable or sensitive cells, the resistant cells will start multiplying and, in the end, make up most of the tumor. These cells continue to grow and spread. 

Tumor Microenvironment

The conditions in the area around the tumor (its microenvironment) may change during treatment. For example, certain types of cells can protect the tumor against attacks by the immune system. Changes that recruit more of these cells to the tumor may include resistance to treatments.

Cancer Stem Cells

In addition to different genetic characteristics within cancer cell populations, there are also specific types of cancer cells called cancer stem cells that may live inside a tumor.

Cancer stem cells have unique properties that give them a special edge against drugs like chemotherapies. They may be some of the last remaining cancer cells after treatment ends, and they can continue to grow, divide, and repopulate a tumor. 

Extrinsic Drug Resistance

Extrinsic drug resistance, which develops within cells in response to the treatment, is often caused by mutations to the genes or changing their protein expression to neutralize the drugs. Extrinsic drug resistance can develop at any time. A tumor may even develop multiple lines of resistance. 

Extrinsic mechanisms of cancer drug resistance include: 

Inactivating Drugs

The cancer cells may start producing proteins (or higher levels of proteins) that can inactivate, block, or break the anticancer drugs, reducing how effective the drugs are. The cells may shuttle the drugs into separate compartments inside the cell to stop them from having their intended effects.

Turning Off Cell Death 

Instead of blocking the action of the drug itself, some cancer cells may turn off the cell-death mechanism (called apoptosis), which is what kills the cell. Many drugs work by causing damage that leads the cells to kill themselves. If the pathways that cause this cell death are turned off, the cells can't kill themselves.

Metabolizing Drugs

The cancer cells may change the way they interact with anticancer drugs to make the drugs less effective. Some drugs need to be modified within the cell to be activated and have their anticancer effects. Without this metabolism by the cell, the drugs are ineffective.

Changing Drug Targets

Mutations to the anticancer drugs' target proteins can reduce how well the drugs work by not allowing them to bind as well to their target. If the binding isn't as strong, the drug will be less effective.

The cells may stop expressing the target molecule altogether. For example, estrogen or progesterone receptors in breast cancers are the target of hormone therapies.

Ramping Up DNA Repair

Many anticancer drugs work by damaging the cancer cell's genes to the point that the cell kills itself. By enhancing their DNA repair mechanisms, the cancer cells may make these drugs less effective.

Gene Amplification

By making additional copies of (amplifying) the gene that makes the anticancer drug's target protein, the cancer cells make more of the target protein to compensate for the drug's effects.

Tweaking Protein and Gene Expression

Epigenetic alterations that cause drug resistance are changes that impact the numbers of certain proteins that are made within the cell.

These kinds of gene expression changes can also be performed by unique RNA-based structures in the cell called microRNA. These changes can ramp up or down the number of proteins being created from any given gene.

Changing the Drug Shuttles

Sometimes, changes in cancer cells can reduce the concentrations of drugs inside cells. This reduction can occur by reducing the number of proteins on the outside of the cell that let the drug in or by increasing the number of proteins that pump drugs out. 

These changes would happen by ramping up or down the expression of a given gene—how many times it is made into a protein—or amplifying the gene.

One major player in changing drug concentrations inside cancer cells is a gene called MDR1 (multiple drug resistance). MDR1 can stop drugs from entering cells and eject drugs from cells.

Fighting Cancer Drug Resistance

There are several approaches that your doctor might take if your tumor stops responding to chemotherapy or other drugs. Many other approaches to drug resistance are still being tested in cells, animals, or clinical trials. 

Combining cancer drugs by treating tumors with multiple chemotherapy drugs at once, also called combination chemotherapy, can disable the cancer cells’ defenses before they get a chance to fight back. Using drugs that work in different ways can also help reduce side effects and improve treatment responsiveness.

Researchers are working on other ways to get around drug resistance. These aren’t likely to be treatments your doctor can use right now if you’ve already developed resistance, but they may be helpful in the future. 

To make cancer treatments work better, researchers are testing drugs in clinical trials that block the mechanisms that cancer cells use to reduce the amount of the drug inside cancer cells.

If a cancer cell changes its epigenetics to escape the effects of a drug, this process may potentially be reversed. Drugs currently in clinical trials might be able to erase or undo these modifications and reset specific resistance pathways, making the cancer cells sensitive to the drug again.

Some tumors may be protected against the immune system by cells like the myeloid cells, which inactivate T cells. T cells are a type of white blood cell that can kill or organize attacks against cancer cells. Drugs that alter the actions of these myeloid cells would let the T cells do their job again, a promising therapy still being developed in animal models.

Because any given patient can develop resistance through several pathways, the best treatment may be multiple treatments used together.

By simultaneously testing multiple anticancer and anti-resistance drug combinations in cell lines created from the patient’s tumor, researchers think they can hone in on effective treatment options. This idea is still being investigated in cells.


Even if your tumor has shrunk or stopped growing in the past, cancer can become resistant to chemotherapy treatments and begin growing again. If tumor growth restarts, your doctor will likely change your treatment approach.

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. 

If your cancer becomes resistant to chemotherapy, your doctor may put you on drugs that work in different ways, or a combination of drugs may be tried. 

A Word From Verywell

Hearing that chemotherapy has failed is a hard truth that some cancer patients have to deal with. It doesn’t mean it’s the end of the road for your treatment, but it does mean your plans will have to change. 

Ask your care team if you have questions about what the next steps are in dealing with your chemo-resistant cancer. 

Frequently Asked Questions

  • Can tumors become resistant to a drug?

    Yes, drug resistance is one of the biggest problems in cancer care today. There are many ways that cancers develop drug resistance. 

  • How do you overcome drug resistance?

    Cancers that become resistant to a given drug are usually still sensitive to other drugs with different pathways. Giving multiple drugs in combination can help overcome the resistance that may develop. 

  • What happens when cancer treatment stops working?

    When cancer treatments stop working, a doctor will likely change your treatment plan to try different treatments that work through different pathways.

  • Which cancer is most resistant to chemotherapy?

    There are no studies that show what cancers are the most resistant to chemotherapy, but advanced cancers like ovarian cancer almost always end up developing resistance to treatments.

5 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. Cancer Quest. Cancer drug resistance

  2. National Cancer Institute. Why do cancer treatments stop working? Updated December 21, 2016.

  3. Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The different mechanisms of cancer drug resistance: A brief review. Adv Pharm Bull. 2017;7(3):339-348. doi:10.15171/apb.2017.041

  4. De Cicco P, Ercolano G, Ianaro A. The new era of cancer immunotherapy: Targeting myeloid-derived suppressor cells to overcome immune evasion. Front Immunol. 2020 Jul 30;11:1680. doi:10.3389/fimmu.2020.01680

  5. Moyano‐Galceran L, Pietilä EA, Turunen SP, et al. Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancerEMBO Mol Med. 2020;12(4). doi:10.15252/emmm.201911177

By Jennifer Welsh
Jennifer Welsh is a Connecticut-based science writer and editor with over ten years of experience under her belt. She’s previously worked and written for WIRED Science, The Scientist, Discover Magazine, LiveScience, and Business Insider.