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

Source: https://onco.cc/roadmaps/targeted-therapy-roadmap/  
OnCo record `targeted-therapy-roadmap` (Roadmap). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Targeted drugs switch off the specific broken protein a cancer depends on. The first ones turned a leukaemia into a chronic condition; the field then learned that resistance is the rule, designed drugs around it, and has now reached the drivers that were called impossible to target.

## Summary

Tamoxifen (1977) and trastuzumab (1998) were targeted therapies before the term existed, but imatinib (2001) defined the category: a pill against the one enzyme a cancer cannot live without, matched to the patients whose tumours carry it. EGFR, ALK and BRAF followed within a decade, and with them the lesson that shaped everything since: nearly every targeted drug stops working within months to years, and the mechanism of escape can be read from the tumour and drugged in turn.

The second generation was designed for resistance and the brain: osimertinib, alectinib and lorlatinib, then their use after surgery (ADAURA, ALINA) and after chemoradiation (LAURA). PARP inhibitors made an inherited DNA-repair defect a treatable target; tissue-agnostic approvals made the mutation, not the organ, the indication. The third generation is reaching targets that were called undruggable: KRAS G12C (sotorasib 2021), then G12D and pan-RAS(ON) inhibitors, HIF-2 in kidney cancer, menin in leukaemia, and protein degraders (vepdegestrant, the first approved PROTAC, 2026) that remove a protein rather than block it.

The pace is set by resistance biology, by the combinatorial space of pairings that trials cannot search, by prices that compound over years of therapy, and by biomarkers that must be validated before a drug can be matched to a patient.

## Fields

- Kind: Roadmap
- Last checked: 2026-09-10

## Sources

- Druker et al., imatinib in CML (NEJM 2001): https://www.nejm.org/doi/full/10.1056/NEJM200104053441401

## Connected records

- roadmaps: [Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome](https://onco.cc/roadmaps/epigenetics-roadmap/), [Hormonal therapy roadmap: removing the ovaries → tamoxifen → oral degraders switched by a blood test](https://onco.cc/roadmaps/hormonal-therapy-roadmap/), [KRAS roadmap: undruggable → G12C → pan-RAS](https://onco.cc/roadmaps/kras-roadmap/), [Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/), [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/), [Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch](https://onco.cc/roadmaps/prostate-roadmap/), [Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem](https://onco.cc/roadmaps/tnbc-roadmap/)
- ideas: [A multi-cancer platform trial of adaptive (dose-holiday) therapy](https://onco.cc/ideas/idea-bio1-adaptive-therapy-platform/), [A standing platform trial that assigns treatment by how the tumour escaped](https://onco.cc/ideas/idea-bio1-resistance-platform-trial/), [Combination baskets defined by resistance mechanism rather than by cancer type](https://onco.cc/ideas/idea-tr2-resistance-mechanism-baskets/), [ctDNA-guided dose holidays for lung cancer targeted therapy](https://onco.cc/ideas/idea-bio1-ctdna-adaptive-tki/), [Evolution-guided 'adaptive therapy' dosing tested in randomised phase 2 trials](https://onco.cc/ideas/idea-tr1-adaptive-therapy-randomised-phase-2/), [Forecast the next resistance mutation like the weather](https://onco.cc/ideas/idea-bio1-evolution-forecasting/), [Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later](https://onco.cc/ideas/idea-prostate-hrr-testing-at-metastatic-diagnosis/), [Vaccinate against the resistance mutation before it takes over](https://onco.cc/ideas/idea-bio1-resistance-mutation-vaccine/)
- drugs: [Adagrasib](https://onco.cc/drugs/adagrasib/), [Alectinib](https://onco.cc/drugs/alectinib/), [Amivantamab](https://onco.cc/drugs/amivantamab/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Crizotinib](https://onco.cc/drugs/crizotinib/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/), [Divarasib](https://onco.cc/drugs/divarasib/), [ELI-002 7P](https://onco.cc/drugs/eli-002-7p/), [Elironrasib](https://onco.cc/drugs/elironrasib/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Eprenetapopt](https://onco.cc/drugs/eprenetapopt/), [Erlotinib](https://onco.cc/drugs/erlotinib/), [Gefitinib](https://onco.cc/drugs/gefitinib/), [Imatinib](https://onco.cc/drugs/imatinib/), [Larotrectinib](https://onco.cc/drugs/larotrectinib/), [Lazertinib](https://onco.cc/drugs/lazertinib/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/), [MRTX1133](https://onco.cc/drugs/mrtx1133/), [Neladalkib](https://onco.cc/drugs/neladalkib/), [Olaparib](https://onco.cc/drugs/olaparib/), [Olomorasib](https://onco.cc/drugs/olomorasib/), [Osimertinib](https://onco.cc/drugs/osimertinib/), [Pemigatinib](https://onco.cc/drugs/pemigatinib/), [Pirtobrutinib](https://onco.cc/drugs/pirtobrutinib/), [Selpercatinib](https://onco.cc/drugs/selpercatinib/), [Sotorasib](https://onco.cc/drugs/sotorasib/), [Tamoxifen](https://onco.cc/drugs/tamoxifen/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/), [Vepdegestrant](https://onco.cc/drugs/vepdegestrant/), [Zoldonrasib](https://onco.cc/drugs/zoldonrasib/)
- pathways: [MYC](https://onco.cc/pathways/myc/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [Companion diagnostics](https://onco.cc/technologies/companion-diagnostic/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [De novo designed protein binders](https://onco.cc/technologies/de-novo-protein-design/), [Degrader-antibody conjugate (DAC)](https://onco.cc/technologies/degrader-antibody-conjugate/), [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Molecular glue discovery platforms](https://onco.cc/technologies/molecular-glue-platforms/), [Oligonucleotide therapeutics](https://onco.cc/technologies/antisense-sirna/), [PARP inhibitors](https://onco.cc/technologies/parp-inhibitor/), [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- targets: [ALK](https://onco.cc/targets/alk/), [BRAF](https://onco.cc/targets/braf/), [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [BTK (Bruton tyrosine kinase)](https://onco.cc/targets/btk/), [EGFR](https://onco.cc/targets/egfr/), [FLT3](https://onco.cc/targets/flt3/), [HER2](https://onco.cc/targets/her2/), [KRAS](https://onco.cc/targets/kras/), [NTRK](https://onco.cc/targets/ntrk/), [PRMT5 (MTAP-deleted cancers)](https://onco.cc/targets/prmt5-mtap/), [RET](https://onco.cc/targets/ret/), [ROS1](https://onco.cc/targets/ros1/)
- companies: [Black Diamond Therapeutics](https://onco.cc/companies/black-diamond-therapeutics/), [Frontier Medicines](https://onco.cc/companies/frontier-medicines/), [Nuvalent](https://onco.cc/companies/nuvalent/)
- institutions: [OHSU Knight Cancer Institute](https://onco.cc/institutions/ohsu-knight/)
- terms: [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/)
- trials: [ADAURA](https://onco.cc/trials/adaura/), [ALINA](https://onco.cc/trials/alina/), [ALKOVE-1](https://onco.cc/trials/alkove-1/), [BRUIN CLL-321](https://onco.cc/trials/bruin-cll-321/), [CaDAnCe-304](https://onco.cc/trials/cadance-304/), [CodeBreaK 200](https://onco.cc/trials/codebreak-200/), [CodeBreaK 300](https://onco.cc/trials/codebreak-300/), [COMBI-AD](https://onco.cc/trials/combi-ad/), [DREAMseq (ECOG-ACRIN EA6134)](https://onco.cc/trials/dreamseq/), [FLAURA2](https://onco.cc/trials/flaura2/), [Gefitinib vs gefitinib plus pemetrexed-carboplatin in EGFR-mutant lung cancer (Tata Memorial)](https://onco.cc/trials/gefitinib-chemo-tmh/), [HERA, NSABP B-31 & NCCTG N9831 (adjuvant trastuzumab)](https://onco.cc/trials/hera-b31-n9831/), [INSIGHT](https://onco.cc/trials/insight-gist/), [Krascendo 1](https://onco.cc/trials/krascendo-1/), [KRYSTAL-12](https://onco.cc/trials/krystal-12/), [LAURA](https://onco.cc/trials/laura/), [LIBRETTO-431](https://onco.cc/trials/libretto-431/), [LITESPARK-005](https://onco.cc/trials/litespark-005/), [MARIPOSA](https://onco.cc/trials/mariposa/), [OlympiA](https://onco.cc/trials/olympia/), [PROfound](https://onco.cc/trials/profound/), [RASolute 302](https://onco.cc/trials/rasolute-302/), [SERENA-6](https://onco.cc/trials/serena-6/), [SOLO-1](https://onco.cc/trials/solo-1/), [TeliMET NSCLC-01](https://onco.cc/trials/telimet-nsclc-01/), [ToGA](https://onco.cc/trials/toga/), [VERITAC-2](https://onco.cc/trials/veritac-2/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Prices and value](https://onco.cc/bottlenecks/b-drug-pricing/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- key papers: [Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib](https://onco.cc/key-papers/paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004/), [EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy](https://onco.cc/key-papers/paper-paez-egfr-mutations-gefitinib-science-2004/), [Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer](https://onco.cc/key-papers/paper-soda-eml4-alk-fusion-nature-2007/), [Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer](https://onco.cc/key-papers/paper-sandler-ecog-4599-bevacizumab-nsclc-nejm-2006/)

---
JSON: https://onco.cc/api/v1/entities/targeted-therapy-roadmap.json