Resistance to cancer drugs
Why tumours stop responding to chemotherapy and targeted drugs: efflux pumps, target mutations, bypass pathways, repair and escape from cell death.
Most deaths from advanced cancer come from tumours that no longer respond to treatment. Resistance can be present from the start (intrinsic) or appear during treatment (acquired), when a few resistant cells survive and regrow. Understanding the mechanism guides the next choice: switching class, combining drugs or testing the tumour again.
Mechanisms in cytotoxic therapy
- Efflux: P-glycoprotein and related ABC transporters pump out anthracyclines, vinca alkaloids, taxanes and etoposide
- Less uptake or activation: for example lower activation of antimetabolite prodrugs
- More inactivation: cells raise detoxifying enzyme systems that neutralise platinum and alkylating agents
- Target change: more dihydrofolate reductase (methotrexate) or altered topoisomerase
- Better DNA repair after platinum and alkylating damage
- Escape from apoptosis: loss of p53 function or excess anti-apoptotic proteins
Mechanisms with targeted therapy
Targeted drugs block one protein that drives the tumour, so they are vulnerable to small changes. The National Cancer Institute describes two main routes: the target protein mutates so the drug can no longer bind, or the cancer finds a different way to grow that does not depend on the target. Known examples are the EGFR T790M mutation in lung cancer and the BCR-ABL T315I mutation in chronic myeloid leukaemia, each answered by a newer inhibitor designed for the changed site.
Hormone therapy resistance
Breast cancers treated with tamoxifen or aromatase inhibitors can acquire oestrogen-receptor mutations or use growth-factor pathways instead. Prostate cancers on androgen deprivation can amplify the androgen receptor or make their own androgens; abiraterone (blocks androgen synthesis) and enzalutamide (blocks the receptor) act at these escape routes.
Strategies against resistance
- Combinations of drugs with different mechanisms, from the start
- Biomarker testing of the tumour, and repeat testing (tissue or blood) when it progresses
- Next-generation inhibitors aimed at known resistance mutations
- Adding immunotherapy or targeted drugs to chemotherapy
- Treating to full planned intensity when possible, since under-treatment favours surviving resistant clones
Test yourself
Think of the answer, then tap the question to see it.
What is multidrug resistance in cancer, and which transporter is the classic cause?
Resistance to several structurally unrelated cytotoxics at once; P-glycoprotein (ABCB1/MDR1) pumping them out of the cell is the classic cause.
What are the two main ways tumours escape targeted therapy?
A mutation in the target that stops the drug binding, and activation of an alternative growth pathway that does not need the target.
Why is a progressing tumour sometimes tested again?
To find the new resistance mechanism (such as a target mutation) that may be treatable with a different drug.
How can prostate cancer escape androgen deprivation?
By amplifying or mutating the androgen receptor, or by making androgens itself; abiraterone and enzalutamide act against these routes.
Example drugs
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Targeted Therapy to Treat Cancer (National Cancer Institute (NCI), 2026); Biomarker Testing for Cancer Treatment (National Cancer Institute (NCI), 2024).
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Representative model, for educational purposes only.