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KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021. This dossier gathers the 24 products (11 approved), 108 trials, 26 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.
Small GTPase switch; oncogenic mutations lock it in the GTP-bound ON state. Adaptive feedback and secondary mutations drive resistance.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Pancreatic ductal adenocarcinoma | 88-94% | Activating mutation (any allele) | 88% of 3,594 targeted-panel samples (Singhi 2019); 2,217 of 2,483, 89.3%, in the Caris cohort (Philip 2022); more than 90% of 109 microdissected exomes (Witkiewicz 2015); cBioPortal: 2,188 of 2,336, 93.7%, in pdac_msk_2024; 361 of 395, 91.4%, in pancreas_msk_2024; 135 of 140, 96.4%, in paad_cptac_2021; 344 of 383, 89.8%, in paad_qcmg_uq_2016; 100 of 109, 91.7%, in paad_utsw_2015; 94 of 99, 94.9%, in paad_icgc. A subset of tumours carries multiple KRAS mutations, some biallelic (Cancer Genome Atlas 2017); mutant KRAS copy gains were recorded in 296 of 853 dosage-annotated pdac_msk_2024 samples (2 or more extra copies in 201, 3 or more in 95). | doi.org |
| Pancreatic ductal adenocarcinoma | 85-90% | Any KRAS mutation | G12D ~40%, G12V ~30%, G12R ~15%, G12C ~1-2% | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 49-59% | G12V, G12D, G12A, G13X and Q61X (share of KRAS mutation records) | cBioPortal, mutation records in luad_mskcc_2023_met_organotropism: G12V 119 of 797 (14.9%), G12D 97 (12.2%), G12A 72 (9.0%), G13C 32 (4.0%), Q61H 30 (3.8%), G13D 30 (3.8%), G12R 11, G12S 10, G12F 6, Q61L 6. In lung_msk_2017: G12D 37 of 244 (15.2%), G12V 37 (15.2%), G12A 19, G13D 12, Q61H 11. | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 41-51% | G12C allele (share of KRAS mutation records) | cBioPortal, mutation records: 344 of 797, 43.2%, in luad_mskcc_2023_met_organotropism; 268 of 526, 50.9%, in nsclc_ctdx_msk_2022; 104 of 244, 42.6%, in lung_msk_2017; 70 of 172, 40.7%, in luad_tcga_pan_can_atlas_2018; 96 of 224, 42.9%, in nsclc_tcga_broad_2016; 36 of 87, 41.4%, in nsclc_pd1_msk_2018. That is about 13% of all lung adenocarcinomas (344 of 2,653 samples in luad_mskcc_2023_met_organotropism). | cBioPortal (TCGA) |
| Colorectal cancer | 40-45% | Any KRAS mutation | G12C ~3-4% | cBioPortal (TCGA) |
| Colorectal cancer | 40-44% | Activating mutation (any allele) | cBioPortal: 3,096 of 7,237, 42.8%, in crc_msk_2026; 495 of 1,134, 43.7%, in crc_msk_2017; 666 of 1,516, 43.9%, in crc_eo_2020; 218 of 534, 40.8%, in coadread_tcga_pan_can_atlas_2018; 94 of 224, 42.0%, in coadread_tcga_pub; 173 of 619, 27.9%, in coadread_dfci_2016; 239 of 1,015, 23.5%, in crc_sysucc_2022. In CO.17, 42.3% of 394 evaluable tumours carried a K-ras exon 2 mutation (Karapetis 2008); ras-gene mutations were present in 58% of adenomas larger than 1 cm but only 9% of adenomas under 1 cm (Vogelstein 1988). | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 39-41% | G12D allele (share of KRAS mutation records) | 889 of 2,188 KRAS mutation records, 40.6%, in pdac_msk_2024 (the study's own KRAS_VARIANT attribute: 892 G12D, 706 G12V, 352 G12R, 111 Q61H, 37 Q61R, 26 G12C, 70 other); 136 of 344, 39.5%, in paad_qcmg_uq_2016; 61 of 135, 45.2%, in paad_cptac_2021; 39 of 95, 41.1%, in paad_icgc; 49 of 119, 41.2%, in paad_tcga_pan_can_atlas_2018; 37 of 100, 37.0%, in paad_utsw_2015 (cBioPortal). Among 219 advanced patients genotyped on EUS-guided biopsies, G12D 73, G12V 53, G12R 21 (Bournet 2016). | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 28-37% | G12V allele (share of KRAS mutation records) | 709 of 2,188, 32.4%, in pdac_msk_2024; 108 of 344, 31.4%, in paad_qcmg_uq_2016; 40 of 135, 29.6%, in paad_cptac_2021; 35 of 95, 36.8%, in paad_icgc; 33 of 119, 27.7%, in paad_tcga_pan_can_atlas_2018; 40 of 100, 40.0%, in paad_utsw_2015 (cBioPortal, mutation records). 53 of 147 codon-12 mutations in 219 advanced patients (Bournet 2016). | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 27-33% | Activating mutation (any allele) | cBioPortal: 787 of 2,653, 29.7%, in luad_mskcc_2023_met_organotropism; 241 of 915, 26.3%, in lung_msk_2017; 168 of 566, 29.7%, in luad_tcga_pan_can_atlas_2018; 75 of 230, 32.6%, in luad_tcga_pub; 33 of 110, 30.0%, in luad_cptac_2020; 33 of 302, 10.9%, in luad_oncosg_2020; 17 of 232, 7.3%, in lung_nci_2022. The Lung Cancer Mutation Consortium found KRAS in 182 of 733 fully genotyped adenocarcinomas, 25%, the commonest single driver in that series (Kris 2014). | cBioPortal (TCGA) |
| Colorectal cancer | 27-29% | G12D allele (share of KRAS mutation records) | cBioPortal, mutation records: 908 of 3,169, 28.7%, in crc_msk_2026; 137 of 504, 27.2%, in crc_msk_2017; 191 of 680, 28.1%, in crc_eo_2020; 58 of 223, 26.0%, in coadread_tcga_pan_can_atlas_2018; 45 of 177, 25.4%, in coadread_dfci_2016; 73 of 243, 30.0%, in crc_sysucc_2022. | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 25-30% | Adenocarcinoma, any KRAS mutation | G12C ~13% of adenocarcinoma | cBioPortal (TCGA) |
| Colorectal cancer | 16-24% | G13D allele (share of KRAS mutation records) | cBioPortal, mutation records: 569 of 3,169, 18.0%, in crc_msk_2026; 90 of 504, 17.9%, in crc_msk_2017; 118 of 680, 17.4%, in crc_eo_2020; 37 of 223, 16.6%, in coadread_tcga_pan_can_atlas_2018; 43 of 177, 24.3%, in coadread_dfci_2016; 55 of 243, 22.6%, in crc_sysucc_2022. | cBioPortal (TCGA) |
| Colorectal cancer | 16-22% | G12V allele (share of KRAS mutation records) | cBioPortal, mutation records: 622 of 3,169, 19.6%, in crc_msk_2026; 101 of 504, 20.0%, in crc_msk_2017; 140 of 680, 20.6%, in crc_eo_2020; 49 of 223, 22.0%, in coadread_tcga_pan_can_atlas_2018; 24 of 177, 13.6%, in coadread_dfci_2016; 38 of 243, 15.6%, in crc_sysucc_2022. | cBioPortal (TCGA) |
| Endometrial cancer | 15-20% | Any KRAS mutation | cBioPortal (TCGA) | |
| Colorectal cancer | 16-18% | Codon 59, 61, 117 or 146 mutation (share of KRAS missense records) | cBioPortal, missense records: 491 of 3,155, 15.6%, in crc_msk_2026 (codons 59 and 61, 152; codons 117 and 146, 270; other, 69); 85 of 503, 16.9%, in crc_msk_2017; 17 of 93, 18.3%, in coadread_tcga_pub; 104 of 676, 15.4%, in crc_eo_2020. A146T alone is 185 of 3,169 KRAS records in crc_msk_2026 and 33 of 504 in crc_msk_2017. | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 12-21% | G12R allele (share of KRAS mutation records) | 354 of 2,188, 16.2%, in pdac_msk_2024; 61 of 344, 17.7%, in paad_qcmg_uq_2016; 23 of 135, 17.0%, in paad_cptac_2021; 16 of 95, 16.8%, in paad_icgc; 25 of 119, 21.0%, in paad_tcga_pan_can_atlas_2018; 12 of 100, 12.0%, in paad_utsw_2015 (cBioPortal, mutation records). G12R is almost unique to pancreatic cancer among KRAS-driven tumours and carried the longest survival of the codon-12 alleles, 14 months, in 219 advanced patients (Bournet 2016). | cBioPortal (TCGA) |
| Ovarian cancer | 10-15% | Low-grade serous and mucinous | cBioPortal (TCGA) | |
| Gallbladder cancer | 11% | Mutation (amplification rarer) | 11% of 244 samples (Giraldo 2022; cBioPortal gbc_mskcc_2022: mutation in 18 of 244, 7.4%, and amplification in 10 of 244, 4.1%); 7.8% of 57 (Li 2014); 7% of 376 Indian patients (Suryavanshi 2025); 7.8% of 103 samples in cBioPortal gbc_msk_2018. | doi.org |
| Pancreatic ductal adenocarcinoma | 6-12% | No KRAS mutation (fusion and alternative-driver search) | 266 of 2,483, 10.7% (Philip 2022); 12% of 3,594 (Singhi 2019); 148 of 2,336, 6.3%, in pdac_msk_2024; 39 of 383, 10.2%, in paad_qcmg_uq_2016; 5 of 99 by the study's KRAS_MUTATION attribute in paad_icgc; 34 of 395, 8.6%, in pancreas_msk_2024 (cBioPortal). Among KRAS wild-type tumours: TP53 mutated in 44.5%, BRAF in 13.0%, fusions of BRAF 6.6%, FGFR2 5.2%, ALK 2.6%, RET 1.3% and NRG1 1.3%, amplification of FGF3 3%, ERBB2 2.2%, FGFR3 1.8%, NTRK 1.8% and MET 1.3%; MSI-high 4.7% against 0.7% and TMB-high 4.5% against 1% in KRAS-mutant disease (Philip 2022). KRAS wild-type TCGA tumours carried GNAS, BRAF, CTNNB1 and other RAS-pathway alterations (Cancer Genome Atlas 2017); all 4 of 17 young adults (Heining 2018) and all 3 of 47 patients (Jones 2019) with wild-type tumours carried a kinase or NRG1 fusion on whole-genome sequencing. | doi.org |
| Colorectal cancer | 6-9% | G12C allele (share of KRAS mutation records) | cBioPortal, mutation records: 219 of 3,169, 6.9%, in crc_msk_2026; 32 of 504, 6.3%, in crc_msk_2017; 42 of 680, 6.2%, in crc_eo_2020; 15 of 223, 6.7%, in coadread_tcga_pan_can_atlas_2018; 16 of 177, 9.0%, in coadread_dfci_2016; 13 of 243, 5.3%, in crc_sysucc_2022. That is about 3% of all colorectal cancers. Among 839 KRAS-mutant metastatic patients, 145, 17%, carried G12C, more often men and with lung and liver metastases, and their overall survival was shorter than with other KRAS alleles (hazard ratio 1.32) (Schirripa 2020). | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 5-8% | Q61H, Q61R, Q61L or Q61K allele (share of KRAS mutation records) | 167 of 2,188, 7.6% (Q61H 107, Q61R 38, Q61L 14, Q61K 8), in pdac_msk_2024; 23 of 344, 6.7% (Q61H 19), in paad_qcmg_uq_2016; 8 of 135, 5.9%, in paad_cptac_2021; 5 of 95, 5.3%, in paad_icgc; 8 of 119, 6.7%, in paad_tcga_pan_can_atlas_2018; 7 of 100, 7.0%, in paad_utsw_2015 (cBioPortal, mutation records). Codon 61 alleles were selectively associated with improved survival among 109 microdissected cancers (Witkiewicz 2015). | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 1-2% | G12C allele (share of KRAS mutation records) | About 1 to 2% of pancreatic cancers (Strickler 2023); 28 of 2,188 KRAS mutation records, 1.3%, and 26 of 2,194 samples with a KRAS_VARIANT call, 1.2%, in pdac_msk_2024; 6 of 344, 1.7%, in paad_qcmg_uq_2016; 4 of 100, 4.0%, in paad_utsw_2015; 3 of 361 in pancreas_msk_2024; 1 of 135 in paad_cptac_2021; 1 of 119 in paad_tcga_pan_can_atlas_2018 (cBioPortal). CodeBreaK 100 treated 38 previously treated patients: 8 centrally confirmed responses, 21%, progression-free survival 4.0 months, overall survival 6.9 months (Strickler 2023); KRYSTAL-1 gave 7 of 21 pancreatic responses, 33.3%, to adagrasib (Bekaii-Saab 2023). | doi.org |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
| 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).
| Modality | Approved | Phase 3 | Phase 2 | Phase 1 |
|---|---|---|---|---|
| Small molecule 18 | ||||
| Test or device 4 | - | - | - | |
| not stated 1 | - | - | - | |
| Vaccine or virus 1 | - | - | - |
| Trial | 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. | |
CAIRO5 NCT02162563 | 3 | Mixed | Initially unresectable colorectal liver metastases, stratified by sidedness and RAS/BRAF status: a doublet plus bevacizumab, FOLFOXIRI plus bevacizumab, or a doublet plus panitumumab, with central resectability review every two months | FOLFOXIRI plus bevacizumab better than a doublet for right-sided or RAS/BRAF-mutant disease; panitumumab no better than bevacizumab for left-sided wild-type disease. | |
CodeBreaK 300 NCT05198934 | 3 | Positive | KRAS G12C colorectal cancer, previously treated: sotorasib + panitumumab vs standard of care | PFS HR 0.49. | |
| 3 | Positive | Locally advanced or metastatic KRAS wild-type pancreatic cancer: nimotuzumab plus gemcitabine versus placebo plus gemcitabine | Overall survival improved with nimotuzumab plus gemcitabine in KRAS wild-type disease. | ||
CodeBreaK 200 NCT04303780 | 3 | Positive | Previously treated KRAS G12C NSCLC: sotorasib vs docetaxel | PFS HR 0.66; OS HR 1.01. | |
New EPOC ISRCTN22944367 | 3 | Negative | KRAS wild-type resectable or suboptimally resectable colorectal liver metastases: perioperative chemotherapy with or without cetuximab | Median overall survival 55.4 months with cetuximab against 81.0 months without (hazard ratio 1.45). | |
CALGB/SWOG 80405 NCT00265850 | 3 | Mixed | KRAS wild-type untreated advanced or metastatic colorectal cancer: cetuximab against bevacizumab, each added to physician-chosen mFOLFOX6 or FOLFIRI | Median overall survival 30.0 with cetuximab against 29.0 months with bevacizumab: no significant difference. | |
PETACC-8 NCT00265811 | 3 | Negative | Resected stage III colon cancer: FOLFOX4 with or without cetuximab | No disease-free survival benefit from cetuximab in KRAS wild-type disease (hazard ratio 1.05). | |
PRIME NCT00364013 | 3 | Positive | Previously untreated metastatic colorectal cancer: FOLFOX4 with or without panitumumab, analysed by extended RAS status | In RAS wild-type disease, overall survival 26.0 against 20.2 months (hazard ratio 0.78); patients with non-exon-2 RAS mutations did worse with panitumumab. | |
Alliance N0147 NCT00079274 | 3 | Negative | Resected stage III colon cancer: mFOLFOX6 with or without cetuximab, by KRAS status | Three-year disease-free survival 71.5 with cetuximab against 74.6 percent without, in KRAS wild-type disease. | |
MRC COIN ISRCTN27286448 | 3 | Negative | Oxaliplatin-based first-line chemotherapy with or without cetuximab in advanced colorectal cancer, with a third arm of intermittent chemotherapy; the primary comparison was in KRAS wild-type tumours | No overall survival gain from adding cetuximab to oxaliplatin-based first-line chemotherapy, including in KRAS wild-type disease. | |
CRYSTAL & FIRE-3 NCT00154102 | 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. | |
NCIC CO.17 NCT00079066 | 3 | Positive | Pretreated EGFR-positive metastatic colorectal cancer with no remaining standard option: cetuximab with best supportive care against best supportive care alone | Overall survival hazard ratio 0.77 (95% CI 0.64 to 0.92, p=0.005) against best supportive care alone; benefit confined to KRAS wild-type tumours. | |
| 3 | Recruiting | A Phase 3, Randomized, Open-label, Multicenter Clinical Study to Evaluate the Safety and Efficacy of MK-1084 in Combination With Subcutaneous Pembrolizumab and Berahyaluronidase Alfa (MK-3475A) Versus MK-3475A in Combination With Pemetrexed/Platinum (Carboplatin or Cisplatin) Chemotherapy as First-line Treatment of Participants With KRAS G12C-Mutant, Advanced or Metastatic Nonsquamous NSCLC (KANDLELIT-007) | - | ||
| 3 | Recruiting | A Phase 3, Randomized, Open-label, Multicenter Clinical Study to Evaluate the Safety and Efficacy of MK-1084, Cetuximab, and mFOLFOX6 Versus mFOLFOX6 With or Without Bevacizumab as First-line Treatment of Participants With KRAS G12C-mutant, Locally Advanced Unresectable or Metastatic Colorectal Cancer (KANDLELIT-012) | - | ||
| 3 | Recruiting | A Phase 3, Randomized, Double-blind, Placebo- and Active-Comparator-Controlled Study of MK-1084 Plus Durvalumab Versus Placebo Plus Durvalumab in Participants With Locally Advanced, Unresected KRAS G12C-Mutant Non-Small Cell Lung Cancer Without Disease Progression Following Definitive Platinum-Based Chemoradiotherapy (KANDLELIT-015) | - | ||
| 3 | Recruiting | A Phase 3, Multicenter, Randomized, Open-label Study Evaluating Efficacy of Sotorasib Platinum Doublet Combination Versus Pembrolizumab Platinum Doublet Combination as a Front-Line Therapy in Subjects With Stage IV or Advanced Stage IIIB/C Nonsquamous Non-Small Cell Lung Cancers, Negative for PD-L1, and Positive for KRAS p.G12C (CodeBreaK 202) | - | ||
| 3 | Recruiting | A Phase III, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Patients With Previously Untreated, KRAS G12C-Mutated, Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer | - | ||
| 3 | Recruiting | A Randomized, Double-Blind, Phase 3 Trial of Adagrasib Plus Pembrolizumab Plus Chemotherapy vs. Placebo Plus Pembrolizumab Plus Chemotherapy in Participants With Previously Untreated, Locally Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer With KRAS G12C Mutation (KRYSTAL-4) | - | ||
| 3 | Recruiting | A Phase 3, Randomized, Double-blind, Multicenter Study of MK-1084 in Combination With Pembrolizumab Compared With Pembrolizumab Plus Placebo as Firstline Treatment of Participants With KRAS G12C-Mutant, Locally Advanced or Metastatic NSCLC With PD-L1 TPS ≥50% (KANDLELIT-004) | - | ||
| 3 | Recruiting | SUNRAY-01, A Global Pivotal Study in Participants With KRAS G12C-Mutant, Locally Advanced or Metastatic Non-Small Cell Lung Cancer Comparing First-Line Treatment of LY3537982 and Pembrolizumab vs Placebo and Pembrolizumab in Those With PD-L1 Expression ≥50% or LY3537982 and Pembrolizumab, Pemetrexed, Platinum vs Placebo and Pembrolizumab, Pemetrexed, Platinum Regardless of PD-L1 Expression | - | ||
| 3 | Recruiting | A Randomized, Open-label, Phase 3 Study of Setidegrasib (ASP3082) Versus Docetaxel in Participants With KRAS G12D-mutated Locally Advanced (Unresectable) or Metastatic Non-small Cell Lung Cancer (NSCLC) Who Have Progressed on or After Platinum Based Chemotherapy and Checkpoint Inhibitor Therapy (CPI) | - | ||
| 3 | Recruiting | A Randomized, Double-Blind, Phase 3 Study of Chemotherapy With or Without INCB161734 in Previously Untreated, KRAS G12D-Mutated Metastatic Pancreatic Ductal Adenocarcinoma (DAWN-303) | - | ||
| 3 | Recruiting | A Phase III, Randomized, Open-Label, Multicenter Study to Evaluate GFH375 Versus Docetaxel in Participants With Locally Advanced and Unresectable or Metastatic Non-Small Cell Lung Cancer With KRAS G12D Mutation Failed Prior Standard Therapy | - | ||
| 3 | Recruiting | A Phase 3, Double-blind, Placebo-controlled, Randomized Study to Assess the Efficacy and Safety of ASP3082 in Combination With mFOLFIRINOX or NALIRIFOX as First-line Treatment in Participants With KRAS G12D Mutated Metastatic Pancreatic Adenocarcinoma | - | ||
| 3 | Recruiting | A Phase III, Randomized, Open-label Study Evaluating the Efficacy and Safety of Divarasib Compared With Investigator's Choice of Immunotherapy or Observation in Patients With Resected Stage II-III KRAS G12C-Positive Non-small Cell Lung Cancer | - | ||
| 3 | Planned | A Randomized, Open-Label, Multicenter Phase III Trial of HRS-7058 Versus the Investigator-Selected KRAS G12C Inhibitor in KRAS G12C-positive Advanced or Metastatic Non-Small Cell Lung Cancer Patients Who Have Failed Standard Treatment | - | ||
| 3 | Recruiting | A Randomized, Controlled, Double-blind, Double-simulated, Multicenter Phase III Clinical Study Evaluating D-1553 Tablet Versus Docetaxel Injection for KRAS G12C Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer After Prior Standard Therapy Failure. | - |
Alternative receptors or downstream mutations re-activate MAPK/PI3K.
Relief of ERK-mediated negative feedback re-activates receptors within hours, producing new wild-type KRAS-GTP the drug cannot bind.
Alter the switch-II pocket or overwhelm the drug.
Alternative MAPK activation.
KEGG's AML map shows the two hits that turn a normal blood stem cell into a leukaemia: a growth signal jammed on (FLT3, KIT or RAS) plus a broken maturation switch (fusion proteins such as PML-RARA or AML1-ETO, or mutated CEBPA and RUNX1). Drugs now exist for both halves.
Which nodes have drugs →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 →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 →This KEGG map shows how chemicals in tobacco smoke, industrial pollutants, plastics and hormones cause cancer without directly damaging DNA: they switch on receptors that drive growth signalling. It matters because these routes explain part of the cancer burden from smoking, dioxins and hormone exposure, and several of the receptors are druggable.
Which nodes have drugs →This KEGG map shows how cancer cells rewire the handling of choline, a nutrient used to build cell membranes, so that growth signals and membrane building feed each other. It matters because the resulting build-up of phosphocholine is visible on MR spectroscopy and PET scans and is one of the metabolic hallmarks of cancer.
Which nodes have drugs →KEGG's CML map is built around one fusion protein, BCR-ABL1, a kinase that never switches off and drives RAS, PI3K and STAT5 signalling. Because a single enzyme causes the disease, a single class of pill (imatinib and its successors) controls it in most patients.
Which nodes have drugs →This KEGG map traces the step-by-step genetic route from normal bowel lining to colorectal cancer: APC loss unleashes Wnt, KRAS mutation drives growth, then TP53 and TGF-beta/SMAD4 loss remove the last brakes, or alternatively mismatch repair fails and mutations pile up. Knowing which route a tumour took decides which drugs work.
Which nodes have drugs →Before a cell divides it must copy three billion letters of DNA exactly once, 'licensing' thousands of start points in advance and firing them in waves. Cancers driven by MYC, cyclin E or RAS fire excess start points too fast, and antimetabolites such as 5-FU, topoisomerase poisons such as irinotecan and platinum drugs all jam this copying machinery.
Which nodes have drugs →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 →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 →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 →KEGG's endometrial cancer map shows oestrogen-related type I tumours with PTEN loss, KRAS and beta-catenin mutations and faulty mismatch repair, and type II tumours with TP53 mutation and HER2 amplification. Immunotherapy for mismatch-repair-deficient tumours and HER2-directed therapy follow directly from this split.
Which nodes have drugs →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 →This KEGG map splits stomach cancer into two routes: the intestinal type that accumulates TP53, APC and HER2 changes step by step, and the diffuse type driven by loss of the cell glue E-cadherin plus MET or FGFR2 amplification. It matters because HER2, FGFR2, claudin 18.2 and PD-1 status now decide first-line treatment.
Which nodes have drugs →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 →This KEGG map shows how hepatitis viruses, alcohol and aflatoxin leave the liver with mutations in telomerase, TP53, Wnt/beta-catenin, PI3K/AKT/mTOR and the oxidative stress sensor NRF2, which together drive liver cancer. It matters because the map explains why liver cancer is treated mainly with angiogenesis blockers and immunotherapy rather than a single targeted drug.
Which nodes have drugs →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 →This KEGG map collects the small RNA molecules (microRNAs) that are switched up or down in nine common cancers and shows which oncogenes and tumour suppressors they silence. It matters because a single microRNA can dial down dozens of genes at once, so losing or gaining one reshapes whole signalling routes.
Which nodes have drugs →KEGG's non-small cell lung cancer map shows a set of alternative on-switches (EGFR mutation, KRAS mutation, EML4-ALK, RET and MET alterations) that all feed the same RAS/ERK, PI3K/AKT and STAT relays, plus loss of the p16 and p53 brakes. Each on-switch now has its own targeted pill, which is why molecular testing comes before treatment.
Which nodes have drugs →This KEGG map shows the order of genetic hits that turn normal pancreatic duct cells into ductal adenocarcinoma: KRAS mutation first, then loss of the p16 brake, then loss of TP53, SMAD4 and BRCA2. It matters because nearly every pancreatic cancer is driven by KRAS, which until recently had no drug.
Which nodes have drugs →This KEGG map shows how sugar-coated proteins on the cell surface and in the surrounding matrix (proteoglycans such as syndecans, glypicans, CD44 and decorin) catch growth factors and hand signals to receptors. It matters because these molecules set how loudly growth signals reach the tumour cell and how easily it invades.
Which nodes have drugs →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 →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 →KEGG's kidney cancer map shows how losing VHL lets the oxygen sensor HIF pile up and order new blood vessels (VEGF, PDGF), while MET and PI3K drive growth in other subtypes. Anti-VEGF drugs, HIF-2a inhibitors and immunotherapy all act on this circuit.
Which nodes have drugs →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 →This KEGG map shows thyroid cancers driven by one relay, the MAPK pathway: RET or NTRK fusions and BRAF mutations in papillary tumours, RAS mutations or PAX8-PPARG fusion in follicular tumours, and TP53 loss marking anaplastic cancer. It matters because RET, NTRK and BRAF alterations each have their own drug, and MAPK blockade can restore iodine uptake.
Which nodes have drugs →| 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) |
| 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. |
Allele matters: G12C lines respond to covalent inhibitors, G12D lines do not; check the allele in DepMap or Cellosaurus before choosing.
Why 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.
Why 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.
Why 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.
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.
The dossier as machine-readable JSON, at /api/v1/dossiers/kras.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-NC 4.0.