Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall

The original targeted cancer drug (1977): a pill that blocks oestrogen's effect on breast cancer and halves recurrence, still essential for premenopausal women.

The first targeted antibody for a solid tumour (1998), which turned HER2-positive breast cancer from the worst subtype into one of the most treatable.

Three trials reported together in 2005 showed that a year of trastuzumab after surgery cuts the risk of dying from HER2-positive breast cancer by about a third.

The trial that brought the breast-cancer drug Herceptin to stomach cancer, the first targeted therapy to improve survival in this disease.

The drug that started the targeted therapy era in 2001, turning chronic myeloid leukaemia into a manageable condition with near-normal life expectancy.

Pills that block the specific enzyme a cancer relies on. Imatinib in 2001 proved a cancer could be switched off by design.

Brian Druker's institute, where imatinib was proven in CML and precision oncology was born; now focused on early detection and functional genomics.

The test that decides whether a specific drug is right for you, approved together with the drug.

The lung-cancer pill whose dramatic responses in a few patients led to the discovery of EGFR mutations in 2004.

Erlotinib was one of the first EGFR pills for lung cancer; it was approved before anyone knew EGFR mutations predicted who would respond, then redefined by them.

A growth receptor that is mutated in some lung cancers and overproduced in others; the first great success of targeted pills.

Crizotinib was the first ALK inhibitor, approved four years after ALK fusions were found in lung cancer; it was also the first drug for ROS1 lung cancer and for ALK-positive lymphoma and inflammatory myofibroblastic tumour in children.

A gene fusion found in about 5% of lung cancers that responds spectacularly to pills, now for many years.

BRAF is a signalling kinase mutated in half of melanomas; blocking it with two drugs at once became a template for targeted therapy.

Dabrafenib plus trametinib is the BRAF-plus-MEK pill combination, approved for BRAF V600E lung cancer and, since 2022, for any solid tumour with that mutation.

Why cancer drugs stop working: the tumour either never depended on the target or evolves around the block.

Nearly every targeted therapy stops working within months to a few years as the tumour adapts.

An Indian trial showed that adding standard chemotherapy to the cheap first-generation pill gefitinib doubled the time lung cancer stayed controlled and cut deaths by more than half.

Osimertinib (Tagrisso) is the standard pill for EGFR-mutant lung cancer, now also given after surgery and with chemotherapy or after chemoradiation.

Alectinib is a well-tolerated ALK pill, standard first line for years and, since 2024, the first targeted therapy given after surgery for ALK-positive lung cancer.

An ALK inhibitor with the longest disease control ever recorded for a targeted lung cancer pill: 60% progression-free at five years.

Showed a targeted pill after lung cancer surgery halves the risk of death, the first such result for a targeted therapy.

Showed that giving an ALK pill after surgery, instead of chemotherapy, sharply reduces recurrence, including in the brain.

For stage III lung cancers with an EGFR mutation, a targeted pill after chemoradiation cut progression by more than 80%.

Pills that block a DNA repair backup, killing cancer cells that already lost their main repair system (BRCA).

Olaparib was the first PARP inhibitor, and turned an inherited BRCA mutation from a risk factor into a drug target, including after surgery in breast cancer.

Two years of an olaparib pill after chemotherapy made a large share of women with BRCA-mutated ovarian cancer long-term survivors.

Showed that a year of a PARP inhibitor after standard treatment improves survival in women with inherited BRCA mutations.

The first biomarker-selected trial in prostate cancer to improve survival, using a PARP inhibitor in men with BRCA-type mutations.

DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum.

The first drug approved for a gene fusion regardless of where the cancer started; it works in about 75% of NTRK-fusion cancers, from infant fibrosarcoma to salivary and thyroid cancers.

Entrectinib (Rozlytrek) is a pill for NTRK-fusion cancers and ROS1 lung cancer that reaches brain metastases.

Selpercatinib is a selective RET inhibitor approved for any tumour with a RET fusion, with a further label update in July 2026.

Proved that a RET pill is better than chemotherapy with or without immunotherapy as first treatment for RET-fusion lung cancer.

A tumour-agnostic approval lets a drug be used for any cancer carrying a specific molecular feature, regardless of where it started.

Rare gene fusions found across dozens of cancer types; the first target where a drug was approved for any tumour carrying it.

RET is a kinase altered in thyroid cancer and a small slice of lung cancer, treatable with one selective pill regardless of where the tumour is.

A gene fusion in about 1-2% of lung cancers that responds for years to targeted pills, now in their third generation.

A year of two targeted pills after surgery halves the risk of relapse in BRAF-mutant melanoma, and the benefit is still visible a decade later.

Settled the order question: for BRAF-mutant melanoma, start with immunotherapy and save the targeted pills for later.

Drugs against the most common cancer gene, considered impossible to target until sotorasib in 2021.

KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021.

Sotorasib (Lumakras) was the first drug to hit KRAS, approved in 2021 after four decades of failure.

Adagrasib was the second KRAS G12C inhibitor, with a long half-life and brain penetration, and is approved in lung and colorectal cancer.

The first randomised trial of a KRAS drug: better than chemotherapy on progression, not on survival.

Confirmed that the KRAS pill adagrasib beats chemotherapy after first-line treatment, though the gain is modest.

Divarasib is Roche's KRAS G12C pill, the first to beat the two approved KRAS drugs head-to-head (July 2026).

The first head-to-head trial among KRAS drugs: Roche's divarasib beat the two approved pills on progression and survival.

CodeBreaK 300 showed that a KRAS drug needs an EGFR antibody partner to work in colorectal cancer.

The first drug aimed specifically at KRAS G12D, the single most common mutation in pancreatic cancer. Early combination data in 2026 showed half of previously treated patients responding.

MRTX1133 was the first potent chemical tool against KRAS G12D, and proved the mutation could be drugged even though it lacks the reactive handle G12C has.

The first drug that blocks all active RAS variants, approved by the FDA in August 2026 for metastatic pancreatic cancer, where KRAS drives 90% of tumours.

The trial that nearly doubled survival in previously treated pancreatic cancer, presented in the ASCO 2026 plenary. The biggest result in the disease's history.

A next-generation KRAS G12C drug that hits the active form of the protein, from the same company as daraxonrasib.

Olomorasib is Lilly's KRAS G12C pill, designed to combine safely with immunotherapy in first-line lung cancer.

The most important cancer gene was declared undruggable for 40 years. Then a pocket was found, and now a pan-RAS drug is in phase 3 for pancreatic cancer.

The HIF-2α inhibitor beat the old standard everolimus after immunotherapy and targeted therapy had failed, with durable responses in a subset.

Instead of blocking a protein, these drugs tag it for the cell's own garbage disposal, removing it entirely.

Vepdegestrant is the first PROTAC ever approved (2026): a pill that tags the oestrogen receptor for destruction, for breast cancers with ESR1 mutations.

The trial that got the first PROTAC approved, with benefit only in tumours with ESR1 mutations.

The first regimen to beat osimertinib in EGFR-mutant lung cancer, with a survival benefit exceeding a year.

A two-armed antibody that blocks EGFR and its escape partner MET, now first-line for EGFR-mutant lung cancer with lazertinib.

A third-generation EGFR pill used together with amivantamab as the first regimen to beat osimertinib in EGFR-mutant lung cancer.

Adding chemotherapy to osimertinib extended both progression-free and, in 2025, overall survival.

A fourth-generation ALK pill that works after lorlatinib and avoids the TRK-related brain side effects; under FDA priority review with a decision due 27 November 2026.

The registrational study of a fourth-generation ALK pill designed to work after lorlatinib and to spare the brain-related side effects.

Designer of cleaner kinase inhibitors; zidesamtinib (ROS1) approved July 2026, neladalkib (ALK) next.

A BTK blocker that works after the older ones stop, because it grips a different part of the enzyme. Fully approved for CLL in December 2025.

The randomised trial that confirmed pirtobrutinib works after other BTK inhibitors fail, leading to full approval in December 2025.

CaDAnCe-304 is the first phase 3 of a protein degrader in leukaemia, pitting BTK destruction against the best available BTK inhibitor.

The signalling enzyme that B-cell cancers use to survive. Blocking it turned chronic lymphocytic leukaemia into a disease controlled by a daily pill.

The confirmatory trial for the first c-MET ADC, which was approved early on response rate alone.

The first trial to change treatment because of a blood test rather than a scan: switching to camizestrant when an ESR1 mutation appeared in the blood delayed progression by seven months.

A blood-test-selected trial testing whether matching the drug to the specific resistance mutation beats the standard second-line drug.

A blood test that reads fragments of DNA shed by the tumour, so you can genotype or monitor cancer without a needle in the tumour.

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.

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

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.

Molecular glues are small molecules that stick two proteins together so the cell destroys one of them. They are smaller and more drug-like than bifunctional degraders.

An ADC that delivers a protein-destroying molecule instead of chemotherapy, hitting targets inside the cell that were previously unreachable.

Oligonucleotide therapeutics are short synthetic strands of genetic code that silence a specific cancer gene.

Designing a protein from scratch on a computer to grip a chosen target, instead of finding one in an animal or a library.

Finding a second gene that a cancer needs only because its first gene is broken, then hitting the second one.

An enzyme that cancers lacking the MTAP gene (about 10-15% of all tumours) depend on more than normal cells do; new inhibitors designed to exploit that difference are in late trials.

Chemoproteomics company with FMC-376, a KRAS G12C inhibitor that hits both the ON and OFF states of the protein, in phase 1/2.

Black Diamond Therapeutics designs cancer pills that hit whole families of mutations in a growth protein at once. Its lead drug, silevertinib, targets mutated EGFR in lung cancer and brain tumours.

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.

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.

Instead of hitting a tumour with the maximum dose until it stops working, adjust the dose to keep the tumour small and let drug-sensitive cells suppress resistant ones. Test this properly across several cancers.

Rather than hitting the tumour as hard as possible, adaptive therapy uses just enough drug to keep it in check, letting drug-sensitive cells suppress resistant ones. A small prostate cancer pilot was promising; randomised trials are needed.

MYC is the most commonly amplified cancer gene, a master switch that turns on thousands of growth genes. It has no pocket for a conventional drug, so it remained 'undruggable' for 40 years; the first direct MYC drugs finally entered trials in the 2020s.

Eprenetapopt (APR-246) was a drug meant to refold mutant p53, the most common broken protein in cancer. Its phase 3 in blood cancer failed in 2020.

The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.

A ready-made vaccine against the seven commonest KRAS mutations, given after pancreatic cancer surgery. Its phase 2 missed the main goal in 2026 but showed signs of activity.

Nearly every targeted therapy stops working within months to a few years as the tumour adapts.

A tumour is many tumours. Treatments that kill most cells leave the rest to grow back, changed.

There are thousands of possible drug pairs and sequences. Trials can test a few dozen a year.

Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab.

New cancer drugs routinely cost over $150,000 a year, often for months of benefit. Systems cannot afford them and patients go bankrupt.

The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.