Acquired resistance to every therapy

Blood tests can already detect tumour DNA. Reporting which sub-populations of the tumour are growing or shrinking, cycle by cycle, would turn the test into an evolution monitor.

Sometimes a progression biopsy shows exactly which drug would help, but it is licensed for another cancer and cannot be obtained. A standing pathway would fix that.

Three antibody-drug conjugates now used in triple-negative breast cancer carry the same kind of chemotherapy warhead, a topoisomerase inhibitor. Nobody has randomised which to give first or whether the second works after the first; small series suggest it often does not. With two now approved first line, the question decides what a patient gets for the rest of her life.

Instead of a new trial for each resistance mechanism, one continuous trial could sort patients into arms based on the reason their last treatment failed.

For each cancer-causing mutation, find every gene the cancer cell newly depends on, in every tissue, so that even undruggable drivers get druggable partners.

When a resistance mutation first appears in the blood, the current drug is often still controlling most of the tumour. Adding a second drug rather than swapping may keep both under control.

If most tumours escape a drug by the same back-up route, blocking that route from the start may prevent resistance rather than chase it.

When a tumour evolves resistance to one drug, it sometimes becomes weaker against another. Map these trade-offs systematically so doctors can pick the next drug to exploit them.

Rather than giving the same dose until the cancer grows, measure tumour DNA in blood every few weeks and let a validated algorithm raise, lower, pause or switch drugs to keep the cancer suppressed for longer.

When a scan shows most tumours shrinking but one growing, that odd lesion holds the escape mechanism. Sampling it, and treating it locally, should be routine.

Cells that survive treatment do so by changing which genes they use, not their DNA. Drugs that block that change may stop survivors from forming at all.

Cancer cells can survive a drug because surrounding normal cells feed them growth signals. Blocking those signals could make existing drugs work better and longer.

Some tumours have broken the machinery that displays their identity to immune cells. Those patients cannot benefit from most immunotherapy and should be routed elsewhere.

Treatment leaves behind damaged cells that stop dividing but do not die, and they release signals that help surviving cancer cells regrow. Removing them could reduce relapse.

Group patients by why their last drug stopped working, then test the combination designed to fix that specific failure, whatever the cancer.

Use tumour DNA in the blood as the signal to pause and restart a lung cancer pill, keeping the tumour in check while slowing the rise of resistant cells.

When attacked, cells switch on a survival programme that buys them time to adapt. Blocking that programme could turn a partial response into a complete one.

Choose two treatments so that whatever the tumour does to escape the first, it becomes easier to kill with the second. The immune system is a good candidate partner.

In advanced prostate cancer the AR-V7 splice variant of the androgen receptor lacks the ligand-binding domain that enzalutamide and abiraterone act on, and its presence predicts resistance. A degrader or N-terminal binder that removes the whole protein, variants included, would still work; AR-V7 is already measurable in circulating tumour cells.

Some cancers escape treatment by changing into a different kind of cell that the drug no longer affects. Tumour RNA in blood could show this shift months before a biopsy would.

When doctors discover how a tumour escaped a drug, that finding usually stops at a paper. Recreating it in a model gives everyone a system to test the next drug against.

Adaptive therapy uses just enough drug to keep a tumour in check, pausing when the burden falls and resuming when it rises, so drug-sensitive cells suppress resistant ones. A prostate cancer pilot with abiraterone lengthened time to progression against historical controls on half the drug; randomised phase 2 trials are the next step.

Cells that receive only a small amount of a drug survive and adapt. Measuring where inside a tumour the drug actually reaches would show where resistance is being bred.

Flu vaccines are chosen by predicting which virus strains will dominate next season. The same forecasting maths could predict which resistance mutation a patient's tumour will develop next.

When a treatment stops working, the tumour is rarely re-sampled, so nobody learns why. Paying for a biopsy at that moment would build the missing map of resistance.

Some patients cannot have their tumour biopsied safely. Cancer cells captured from a blood sample can sometimes be grown into a model instead.

A few cancer cells survive treatment by going quiet rather than mutating. These survivors are unusually vulnerable to a particular kind of cell death, which a drug could trigger.

Resistance mutations often exist in a tiny fraction of cells before treatment starts. Error-corrected sequencing that detects variants below 0.01 percent allele fraction could find them at diagnosis and prompt a mechanism-matched combination from day one.

Drugs approved on early evidence come with follow-up obligations. One of them should be finding out how tumours escape the new drug.

When a targeted drug stops working, the tumour has usually changed in a way you can read. Most patients still move to the next treatment on a protocol rather than on a test of what actually happened.

Knowledge about how cancers become resistant is scattered across thousands of papers and company files. Pooling it into one structured, public resource would let anyone see the pattern.

Resistant cancer cells can become dependent on the drug they resisted, as shown for BRAF-inhibitor-resistant melanoma in mice. Stopping the drug for a defined washout and then rechallenging, while tracking the resistance allele in blood tumour DNA, could make the tumour vulnerable to it once more.

Cell therapies fail when the tumour stops showing the marker they were built to find. Preparing an alternative product in advance would let doctors switch quickly.

Trials usually study one treatment at a time, so nobody knows the best order. Deciding the next step in advance, by lottery, answers the sequencing question at little extra cost.

Metastatic prostate cancer now has six classes of treatment that work, and no trial has ever compared the orders they can be given in. Every trial adds a drug to the front; none asks what should follow it, so the sequence a man receives is decided by habit and by what was licensed first.

The first drug against the KRAS protein nearly doubled survival in pancreatic cancer in 2026, but on its own it holds the disease for months, not years. Trials are now testing it in combination with a second RAS drug and with chemotherapy, and earlier in the disease; the open questions are which combination, in which order, and what works when the tumour escapes.

Antibody drugs need their target to still be present. After one fails, checking which surface markers remain would guide the choice of the next one instead of guessing.

Treatment is often chosen from a biopsy taken years earlier from the original tumour. The spread disease may now look different. Test it again before switching drugs.

Hospitals rotate antibiotics to stop bacteria adapting. Cycling between two cancer drugs on a set schedule, rather than using one until it fails, might work the same way.

Patients are randomised at each decision point, not just at the start, so one trial can compare whole treatment sequences rather than single drugs.

Subsets of lung, bladder and breast cancers carry raised APOBEC enzyme activity that keeps generating new mutations, feeding resistance. Blocking APOBEC3 alongside a targeted drug aims not to kill cells but to slow the rate at which resistant variants arise; the inhibitors are still in discovery.

Real treatment is a series of decisions: start with this, switch to that if it fails. Sequential multiple-assignment randomised trials test whole strategies by randomising patients again at each decision point.

Cells that survive treatment often change how they make energy, relying on burning fat rather than sugar. Blocking that switch might finish them off.

Species go extinct when a second disaster hits a population already shrunk by a first one. Apply the same logic: hit the tumour with a different kind of drug when it is smallest, rather than waiting for it to grow back.

Giving men with castration-resistant prostate cancer large doses of the hormone the treatment has spent years removing makes a third of them respond, and makes half of them respond again to the drug that had stopped working. It has never been taken to a definitive trial, partly because the endpoint that shows the benefit is not the one trials usually use.

Two drugs might work better given in turns rather than together, with less toxicity. Almost no trial has tested this.

Giving a targeted drug in pulses rather than continuously might slow the emergence of resistant cells and reduce side effects. Early results are mixed, so this needs careful trials with clear rules for when to try it.

Targeted drugs briefly make cancer cells easier for the immune system to spot. Giving immunotherapy exactly in that window, rather than at the same time, may work better.

Countries track how bacteria become resistant to antibiotics and publish it. Doing the same for cancer drugs would show which escape routes are becoming common and where.

Under treatment stress, cancer cells switch on sloppy DNA copying that generates the mutations they need to survive. Blocking that machinery could stop resistance being invented.

If a drug relies on one marker, the tumour can survive by dropping it. A drug that recognises two markers at once makes that escape harder.

A single protein predicts whether a tumour will respond to DNA-damaging drug payloads. Measuring it could stop patients receiving a second drug of the same kind that will not work.

Resistance often arrives as the same few mutations. Teaching the immune system to recognise them in advance could remove the escaping cells while they are still rare.

In a minority of men, prostate cancer escapes hormone drugs by becoming a different kind of cell that no longer needs the androgen receptor. By the time a biopsy shows it, the treatment options are almost gone. The genetic changes that allow the switch are detectable years earlier, and nobody is looking for them.

Cancers with faulty DNA proof-reading depend on one particular unwinding enzyme to survive. Blocking it kills them and spares normal cells.