Drivers versus passengers

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.

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.

Aggressive glioblastomas, sarcomas and gastric cancers keep amplified cancer genes such as EGFR, MYC, MDM2 and CDK4 on free-floating DNA circles (ecDNA) whose copy number rises and falls quickly, letting the tumour dial resistance up and down. Cells carrying ecDNA depend on CHK1, giving a first drug target.

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.

The cells that survive targeted therapy change shape and become unusually dependent on an antioxidant enzyme, GPX4. Hitting them in that window might stop resistance before it evolves.

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.

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.

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.

Rather than waiting for resistance to one payload and then switching, give two mechanisms from day one, as HIV therapy does.

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.

Anyone with ovarian, pancreatic, metastatic prostate or mismatch-repair-deficient colorectal cancer should be tested for inherited mutations, yet testing rates fall well short. Making it an automatic, opt-out laboratory step triggered by pathology, as reflex mismatch-repair testing already is, would close the gap.

Pack-year rules miss people who get lung cancer without heavy smoking, including East Asian women who never smoked, as Taiwan's TALENT study showed. Eligibility by a validated risk model with a set threshold, plus a never-smoker arm where family history matters, would find more cancers per scan.

Most people carrying a high-risk cancer gene do not know it until someone in the family gets cancer. Offer testing to all adults so carriers can be protected before that happens.

Sequence every cancer at diagnosis, along with the patient's inherited genes, and pool the results with treatments and outcomes so every patient teaches the system how to treat the next.

Companies and public funders would pool money and scientists to crack the hardest cancer proteins, such as MYC and mutant p53, sharing everything openly until there is a real drug candidate, then competing on the final product.

Drugs are processed differently by people with different genetic backgrounds, but doses are set mostly in white and East Asian populations. Every new drug should be studied for how it behaves across ancestries, with dosing advice by genotype rather than by race.

Stomach cancer now has three add-on biomarkers (HER2, PD-L1, Claudin 18.2) that often overlap. Test whether combining two add-ons beats picking one.

Add immunotherapy to the two targeted pills in the most aggressive thyroid cancer, because the combination has produced multi-year survivors in early series.

One RAS mutation can now be drugged because it offers a reactive handle. Most RAS mutations do not, so new chemistry is needed to grab other amino acids.

Cancer spreading along the linings of the brain is almost untreatable. Injecting engineered immune cells directly into the brain fluid, through a small reservoir, reaches it.