Growth-factor signalling: RTKs and RAS/RAF/MEK

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.

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.

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.

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.

Rare cancers often share a broken cellular machine even when they arise in different organs. Grouping patients by that shared fault makes trials possible.

Serous endometrial cancers often overproduce HER2. Enhertu already works in them; testing HER2 in every p53-abnormal tumour and using the ADC earlier could change outcomes for the worst subtype.

Ninety-five percent of bowel cancers ignore immunotherapy. Combinations that heat the tumour up (targeted drugs, radiation, new checkpoints) are the main hope.

Almost every pancreatic cancer shares one of a handful of KRAS mutations. A pre-made vaccine against them could be given to every patient after surgery.