KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021. This dossier gathers the 10 products (4 approved), 8 trials, 12 pathways and 4 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Biology
Small GTPase switch; oncogenic mutations lock it in the GTP-bound ON state. Adaptive feedback and secondary mutations drive resistance.
- Pancreatic (~90%)
- Colorectal (~40-45%)
- Lung adenocarcinoma (~30%)
- Endometrial, ovarian (subsets)
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Pancreatic ductal adenocarcinoma | 85-90% | Any KRAS mutation | G12D ~40%, G12V ~30%, G12R ~15%, G12C ~1-2% | cBioPortal (TCGA) |
| Colorectal cancer | 40-45% | Any KRAS mutation | G12C ~3-4% | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 25-30% | Adenocarcinoma, any KRAS mutation | G12C ~13% of adenocarcinoma | cBioPortal (TCGA) |
| Endometrial cancer | 15-20% | Any KRAS mutation | cBioPortal (TCGA) | |
| Ovarian cancer | 10-15% | Low-grade serous and mucinous | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Mutation hotspots and which drugs address them
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| G12C 12 | Activating | About 13% of lung adenocarcinomas and 1 to 3% of other solid tumours | Cysteine at codon 12 is what the covalent inhibitors bond to; the first druggable RAS allele. | — | CodeBreaK 100, NEJM 2021 | |
| G12D 12 | Activating | The most common KRAS allele in pancreatic cancer | No cysteine, so the covalent G12C chemistry does not apply; non-covalent G12D-selective and pan-RAS(ON) inhibitors followed. | — | COSMIC: KRAS | |
| G12V 12 | Activating | Second most common allele in pancreatic and colorectal cancer | Addressed only by pan-RAS(ON) inhibitors and mutant-KRAS vaccines so far. | — | COSMIC: KRAS | |
| G12R 12 | Activating | not sourced | Largely pancreatic; biochemically distinct (weak PI3K coupling). | — | COSMIC: KRAS | |
| G13D 13 | Activating | not sourced | Colorectal-enriched; retains some sensitivity to anti-EGFR antibodies in retrospective series, unlike codon 12 alleles. | — | COSMIC: KRAS | |
| Q61H/K/L/R 61 | Activating | not sourced | Switch II; abolishes intrinsic GTP hydrolysis. Rare in KRAS (common in NRAS). | — | COSMIC: KRAS | |
| Y96D / R68S / H95Q 96 | Resistance | not sourced | Acquired switch-II pocket mutations after sotorasib or adagrasib; pan-RAS(ON) tri-complex inhibitors bind a different surface. | Awad et al., NEJM 2021 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: Cancer Hotspots (MSK) · COSMIC: KRAS · Ostrem et al., Nature 2013 (G12C pocket).
Products by modality and phase
Browse products →| Modality | Approved | Phase 3 | Phase 2 | Phase 1 |
|---|---|---|---|---|
| Small molecule 9 | ||||
| Vaccine or virus 1 | — | — | — |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| Krascendo 1 NCT06497556 | 3 | Positive | Previously treated KRAS G12C NSCLC: divarasib vs sotorasib or adagrasib | Superior PFS and OS vs approved G12C inhibitors (topline, July 2026). | |
| RASolute 302 NCT06625320 | 3 | Positive | Metastatic PDAC after one prior line of chemotherapy: daraxonrasib vs investigator's choice chemotherapy | OS 13.2 vs 6.7 months, HR 0.40. | |
| KRYSTAL-12 NCT04685135 | 3 | Positive | Previously treated KRAS G12C NSCLC: adagrasib vs docetaxel | PFS HR 0.58. | |
| CodeBreaK 300 NCT05198934 | 3 | Positive | KRAS G12C colorectal cancer, previously treated: sotorasib + panitumumab vs standard of care | PFS HR 0.49. | |
| CodeBreaK 200 NCT04303780 | 3 | Positive | Previously treated KRAS G12C NSCLC: sotorasib vs docetaxel | PFS HR 0.66; OS HR 1.01. | |
| CRYSTAL & FIRE-3 | 3 | Positive | First-line metastatic colorectal cancer: FOLFIRI ± cetuximab (CRYSTAL); FOLFIRI + cetuximab vs FOLFIRI + bevacizumab (FIRE-3) | CRYSTAL KRAS-WT OS 23.5 vs 20.0 months; FIRE-3 OS 28.7 vs 25.0 months. | |
| AMPLIFY-7P NCT05726864 | 2 | Negative | Adjuvant mKRAS PDAC after surgery and chemotherapy: ELI-002 7P vs observation | Primary DFS endpoint not met. | |
| RAMP 201 NCT04625270 | 2 | Positive | Recurrent low-grade serous ovarian cancer: avutometinib (RAF/MEK clamp) + defactinib (FAK inhibitor) | ORR 44%, median PFS 19.6 months in KRAS-mutant LGSOC. |
Resistance routes that involve this target
Unaddressed routes →Alternative receptors or downstream mutations re-activate MAPK/PI3K.
- Combination with MET or MEK inhibitors (trials); chemotherapy; ADCs
Relief of ERK-mediated negative feedback re-activates receptors within hours, producing new wild-type KRAS-GTP the drug cannot bind.
- Add anti-EGFR antibody in colorectal cancer (CodeBreaK 300, KRYSTAL-1)
- SHP2 or SOS1 inhibitor combinations (trials)
Alter the switch-II pocket or overwhelm the drug.
- Pan-RAS(ON) tri-complex inhibitors (daraxonrasib) bind a different site
Alternative MAPK activation.
- Combination with MEK/ERK inhibitors; re-biopsy-guided therapy
Pathways where it is a node
Pathway-to-drug matrix →- AutophagyNode: Nutrient stress, KRAS/MEK inhibition · 1 druggable nodes
Autophagy is the cell's recycling programme. Cancer cells, especially pancreatic and RAS-driven tumours, use it to survive starvation and drug stress, which is why hydroxychloroquine, an old malaria drug that blocks it, keeps appearing in trials.
Which nodes have drugs → - BCR::ABL1 (Philadelphia chromosome)Node: RAS → MAPK · 2 druggable nodes
Chronic myeloid leukaemia is caused by one broken gene: two chromosomes swap pieces and glue a kinase (ABL1) to a protein that forces it permanently on. Imatinib, the first drug to target it, turned a fatal disease into a manageable one, and later drugs cover the mutations that escape it.
Which nodes have drugs → - DNA replication & origin licensingNode: MYC, cyclin E: excess origins · 3 druggable nodes
Before a cell divides it must copy three billion letters of DNA exactly once. It does this by 'licensing' thousands of start points in advance and then firing them in waves. Cancers fire too many too fast, and many chemotherapies work by starving or jamming the copying machinery.
Which nodes have drugs → - DNA replication stressNode: Oncogenes (MYC, cyclin E, RAS) · 4 druggable nodes
Cancers copy their DNA too fast and with broken checkpoints, so replication forks stall and collapse. They survive only by leaning on emergency repair kinases such as ATR, CHK1, and WEE1, which is why blocking those kinases can be selectively lethal.
Which nodes have drugs → - Drivers, passengers & the two-hit modelNode: Mutation, amp, fusion · 2 druggable nodes
Of the thousands of mutations in a tumour, only a handful (typically 2-8) actually drive it. Drivers either jam an accelerator on (oncogenes, one hit is enough) or remove a brake (tumour suppressors, both copies must go). Everything else is a passenger along for the ride.
Which nodes have drugs → - Drug efflux pumps (ABC transporters)Node: EMT, hypoxia, NRF2 induce · 2 druggable nodes
Cancer cells can install pumps in their outer membrane that throw chemotherapy back out as fast as it comes in. The same pumps guard the gut, brain and bone marrow in healthy tissue, which is why blocking them failed as a strategy and why drug designers now choose payloads the pumps cannot grip.
Which nodes have drugs → - FGF / FGFR signallingNode: GRB2 / SOS → RAS → MAPK · 3 druggable nodes
Fibroblast growth factor receptors are growth antennas on the cell surface. Bladder cancer mutates FGFR3, bile duct cancer fuses FGFR2 to other genes, and stomach cancer overproduces FGFR2b; each has its own drug, and each brings a tell-tale side effect (high phosphate) because the same receptors control phosphate in the kidney.
Which nodes have drugs → - Glutamine addictionNode: MYC, KRAS drive uptake · 4 druggable nodes
After glucose, glutamine is the tumour's favourite food. It feeds the energy cycle, donates nitrogen for making DNA letters, and makes the antioxidant glutathione. MYC- and KRAS-driven cancers eat so much of it that they starve the T cells next door.
Which nodes have drugs → - Lipid synthesis, uptake & cholesterolNode: Mevalonate → cholesterol · 2 druggable nodes
Dividing cells need membranes, and membranes are fat. Cancers switch on the fat-building enzymes most adult tissues keep off, and in fatty environments (breast, omentum, bone marrow) they also steal lipids from neighbouring fat cells. This links obesity to cancer and offers new drug targets.
Which nodes have drugs → - RAS / RAF / MEK / ERK (MAPK)Node: RAS (KRAS) · 3 druggable nodes
The RAS-MAPK pathway is the cell's 'divide' relay. A signal at the surface flips RAS on, which passes to RAF, MEK, and ERK, which tell the nucleus to make the cell divide. KRAS and BRAF mutations jam it in the on position.
Which nodes have drugs → - Receptor tyrosine kinase activationNode: GRB2/SOS → RAS · 5 druggable nodes
Growth-factor receptors are antennas on the cell surface that pair up when a signal lands and switch on the growth relays inside. Cancers mutate, multiply, or fuse these antennas so they broadcast 'grow' with no signal at all. Most targeted drugs, antibodies and ADCs start here.
Which nodes have drugs → - Resistance routes: how a blocked pathway comes backNode: 1 Target mutation / amp · 6 druggable nodes
When a drug blocks a cancer's engine, the cancer has five ways back: change the part the drug binds, make more of it, take a side road, switch to a different engine altogether, or stop letting the drug in. Knowing which route a tumour took decides the next drug.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| therascreen KRAS RGQ PCR Kit QIAGEN · FDA CDx 2012 | PCR | Wild-type required for cetuximab or panitumumab (colorectal); G12C detected for sotorasib and adagrasib (NSCLC) | |
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| Guardant360 CDx Guardant Health · FDA CDx 2020 | NGS plasma | Per companion claim: EGFR (osimertinib), EGFR exon 20 insertions (amivantamab), KRAS G12C (sotorasib), ESR1 mutations (elacestrant), ERBB2 mutations (zongertinib); negative plasma reflexes to tissue | |
| Agilent Resolution ctDx FIRST Agilent (Resolution Bioscience) · FDA CDx 2022 | NGS plasma | KRAS G12C detected (adagrasib, NSCLC) |
Preclinical models
All models →| Cell line | Identifiers | Why it is used |
|---|---|---|
| NCI-H358 | CVCL_1559 · ACH-000860 | Lung, G12C; the sotorasib and adagrasib reference line. |
| MIA PaCa-2 | CVCL_0428 · ACH-000601 | Pancreatic, G12C. |
| NCI-H23 | CVCL_1547 · ACH-000900 | Lung, G12C. |
| SW1573 | CVCL_1720 · ACH-000677 | Lung, G12C. |
| Calu-1 | CVCL_0608 · ACH-000511 | Lung, G12C. |
| AsPC-1 | CVCL_0152 · ACH-000222 | Pancreatic, G12D. |
| PANC-1 | CVCL_0480 · ACH-000164 | Pancreatic, G12D. |
| HPAF-II | CVCL_0313 · ACH-000094 | Pancreatic, G12D. |
| LS180 | CVCL_0397 · ACH-000957 | Colorectal, G12D. |
| SW480 | CVCL_0546 · ACH-000842 | Colorectal, G12V. |
| Capan-1 | CVCL_0237 · ACH-000354 | Pancreatic, G12V. |
| HCT 116 | CVCL_0291 · ACH-000971 | Colorectal, G13D. |
| NCI-H460 | CVCL_0459 · ACH-000463 | Lung, Q61H. |
| A549 | CVCL_0023 · ACH-000681 | Lung, G12S. |
| CT26 Mus musculus | CVCL_7254 | Mouse colon, G12D; syngeneic. |
- Kras LSL-G12D (Conditional G12D allele used across lung, pancreas and colon models) Jackson et al., Genes Dev 2001
- Kras LSL-G12C (Conditional G12C allele) Canon et al., Nature 2019
Allele matters: G12C lines respond to covalent inhibitors, G12D lines do not; check the allele in DepMap or Cellosaurus before choosing.
Open questions
All open questions →- 01
Will KRAS G12D and pan-RAS(ON) inhibitors improve survival in pancreatic cancer, where G12D dominates?
clinicalindustryWhy unresolved. The covalent G12C chemistry does not transfer to G12D, and pancreatic tumours rewire quickly through receptor feedback. Daraxonrasib reached approval on RASolute 302 but durable benefit in first line and in the adjuvant setting is unproven.
What would answer it. Randomised overall-survival data for pan-RAS(ON) or G12D-selective inhibitors in first-line and resected pancreatic cancer, with paired biopsies showing which bypass routes emerge.
Source: RASolute 302 (ClinicalTrials.gov) - 02
Does blocking the adaptive receptor feedback up front (EGFR, SHP2 or SOS1 co-inhibition) beat sequencing after progression?
clinicalindustryWhy unresolved. Relief of ERK feedback re-activates receptors within hours of RAS inhibition; CodeBreaK 300 showed EGFR co-blockade helps in colorectal cancer, but whether that generalises to lung cancer and to SHP2 or SOS1 combinations is open.
What would answer it. Phase 3 comparisons of first-line combinations against single-agent inhibitor followed by combination at progression, with ctDNA to time the switch.
Source: CodeBreaK 300, NEJM 2023 - 03
Can shared-antigen KRAS vaccines prevent relapse after surgery in pancreatic and colorectal cancer?
clinicalresearchWhy unresolved. Mutant KRAS peptides are public neoantigens present in most pancreatic cancers, but AMPLIFY-7P missed its endpoint and it is unclear whether T-cell responses translate into fewer relapses.
What would answer it. Randomised relapse-free-survival data for a KRAS vaccine, with ctDNA clearance as an early read, in resected patients with minimal residual disease.
Source: AMPLIFY-7P (ClinicalTrials.gov)
Ideas and companies
Key papers and the live literature
Preprints →- CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug · The Lancet 2023
- CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer · New England Journal of Medicine 2023
- FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high · New England Journal of Medicine 2021
- Cancer genome landscapes: about 140 driver genes, and each tumour needs only a handful · Science 2013
- Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable · Nature 2013
Query for this target: (TITLE:"KRAS" OR ABSTRACT:"KRAS") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about KRAS, not a curated reading list.
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The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/kras.json. Licence CC BY 4.0.