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 thechemotherapy drugsand 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.
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 havemutations(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
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 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
Metabolizing Drugs
Changing Drug Targets
The cells may stop expressing the target molecule altogether. For example,estrogen or progesterone receptors in breast cancersare the target ofhormone therapies.
Ramping Up DNA Repair
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.
Changing the Drug Shuttles
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.
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.
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.
Summary
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 QuestionsYes, drug resistance is one of the biggest problems in cancer care today. There are many ways that cancers develop 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.When cancer treatments stop working, a doctor will likely change your treatment plan to try different treatments that work through different pathways.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.
Frequently Asked Questions
Yes, drug resistance is one of the biggest problems in cancer care today. There are many ways that cancers develop 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.
When cancer treatments stop working, a doctor will likely change your treatment plan to try different treatments that work through different pathways.
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 SourcesVerywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.Cancer Quest.Cancer drug resistance.National Cancer Institute.Why do cancer treatments stop working?Updated December 21, 2016.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.2017.041De 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.2020.01680Moyano‐Galceran L, Pietilä EA, Turunen SP, et al.Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer.EMBO Mol Med. 2020;12(4). doi:10.15252/emmm.201911177
5 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.Cancer Quest.Cancer drug resistance.National Cancer Institute.Why do cancer treatments stop working?Updated December 21, 2016.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.2017.041De 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.2020.01680Moyano‐Galceran L, Pietilä EA, Turunen SP, et al.Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer.EMBO Mol Med. 2020;12(4). doi:10.15252/emmm.201911177
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read oureditorial processto learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
Cancer Quest.Cancer drug resistance.National Cancer Institute.Why do cancer treatments stop working?Updated December 21, 2016.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.2017.041De 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.2020.01680Moyano‐Galceran L, Pietilä EA, Turunen SP, et al.Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer.EMBO Mol Med. 2020;12(4). doi:10.15252/emmm.201911177
Cancer Quest.Cancer drug resistance.
National Cancer Institute.Why do cancer treatments stop working?Updated December 21, 2016.
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
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
Moyano‐Galceran L, Pietilä EA, Turunen SP, et al.Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer.EMBO Mol Med. 2020;12(4). doi:10.15252/emmm.201911177
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