KRAS
KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021.
KRAS mutations drive ~90% of pancreatic, ~40% of colorectal, and ~30% of lung adenocarcinomas. Sotorasib and adagrasib (G12C) were first; G12D inhibitors (MRTX1133, zoldonrasib) and pan-RAS(ON) inhibitors (daraxonrasib, RMC-6236, in phase 3 in pancreatic cancer) are the next wave. Combination with EGFR antibodies is needed in colorectal cancer.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021.
- 1 · What it is
KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021.
- 2 · What goes wrong in cancer
Small GTPase switch; oncogenic mutations lock it in the GTP-bound ON state. Adaptive feedback and secondary mutations drive resistance.
- 3 · How drugs use it
10 products aim at KRAS: vaccines and small molecules. Drugs fit a pocket that exists only in one shape of the mutant protein and hold it there, off.
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)
How common it is, by cancer
| 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.
Adagrasib was the second KRAS G12C inhibitor, with a long half-life and brain penetration, and is approved in lung and colorectal cancer.
Avutometinib plus defactinib is the first treatment approved specifically for low-grade serous ovarian cancer, a slow-growing type driven by the RAS pathway.
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.
Divarasib is Roche's KRAS G12C pill, the first to beat the two approved KRAS drugs head-to-head (July 2026).
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.
A next-generation KRAS G12C drug that hits the active form of the protein, from the same company as daraxonrasib.
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.
Olomorasib is Lilly's KRAS G12C pill, designed to combine safely with immunotherapy in first-line lung cancer.
Sotorasib (Lumakras) was the first drug to hit KRAS, approved in 2021 after four decades of failure.
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.
Patients with KRAS G12C lung cancer that has progressed after chemo-immunotherapy can take an oral KRAS inhibitor instead of docetaxel and gain a somewhat longer time to progression with fewer severe side effects, but should understand that most tumours become resistant within a year and that survival is not improved. KRAS G12C testing is worthwhile, but first-generation inhibitors are a step rather than a cure; combinations and next-generation inhibitors are the active research fronts.
Patients with metastatic colorectal cancer carrying a KRAS G12C mutation (about 3-4% of cases) who have exhausted standard chemotherapy now have a targeted option that works far better than trifluridine-tipiracil or regorafenib. The higher sotorasib dose is clearly superior, and the EGFR antibody is essential because KRAS inhibition alone barely works in bowel cancer. Responses are still modest and short-lived compared with EGFR or ALK inhibitors in lung cancer.
The dose on the label is often not the best dose for patients; it is the highest one that was tolerable for a few weeks. Project Optimus means new cancer drugs should arrive with evidence on dose, and it gives clinicians licence to consider dose reduction for toxicity. For older drugs, the evidence gap persists.
There are not thousands of cancer genes, and any one patient's tumour is driven by only a few of them. That makes targeted sequencing panels sensible, but because most drivers are lost tumour suppressors, drugs exist for only a minority, which is why the same group turned to early detection.
The most frequently mutated oncogene in cancer stopped being undruggable, and patients with KRAS G12C lung and bowel cancers now have targeted pills. The approach, exploiting a mutation-created chemical handle and an inactive-state pocket, has become a template for other hard targets.
Latest papers
topQuery 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.
Pages like this
not linked directly; found by shared links- TargetEGFR
Shares CodeBreaK 300, John V. Heymach, Pasi A. Jänne, Ryan B. Corcoran and the tag driver.
- TargetBRAF
Shares Elena Élez, Ryan B. Corcoran, Downstream and upstream, Driver mutation and the tag driver.
- TargetALK
Shares LUNGevity Foundation (and GO2 for Lung Cancer), Driver mutation, Oncogene, Hallmark: sustaining proliferative signalling and the tag driver.
- TargetHER2
Shares Tanios Bekaii-Saab, Oncogene, Istituto di Candiolo IRCCS – FPO, Hallmark: sustaining proliferative signalling and the tag driver.
- TargetPIK3CA / PI3K-alpha
Shares Oncogene, Cancer genome landscapes: about 140 driver genes, and each tumour needs only a handful, Hallmark: sustaining proliferative signalling, Resistance routes: how a blocked pathway comes back and the tag driver.
- TargetROS1
Shares LUNGevity Foundation (and GO2 for Lung Cancer), Receptor tyrosine kinase activation, PI3K / AKT / mTOR, RAS / RAF / MEK / ERK (MAPK) and the tag driver.
- TargetFGFR2
Shares Tanios Bekaii-Saab, Receptor tyrosine kinase activation, PI3K / AKT / mTOR, RAS / RAF / MEK / ERK (MAPK) and the tag driver.
- TargetNTRK
Shares Receptor tyrosine kinase activation, RAS / RAF / MEK / ERK (MAPK), Small-molecule kinase inhibitors, Pancreatic ductal adenocarcinoma and the tag driver.