KRAS12p12.1

In brief

The gene and the protein

KRAS is a small protein with a big job. Its 188 or 189 residues sit at the inner face of the cell membrane, where it passes signals from growth factor receptors on the surface to the machinery that decides whether a cell divides. It belongs to the RAS family, with HRAS and NRAS; the catalytic parts of the three are nearly identical, and they differ mostly at the tail ¹.

The name is an accident of virology. In 1967 Werner Kirsten described a mouse virus that caused sarcomas in rats ². In 1982 the transforming genes found in a human bladder carcinoma and a human lung carcinoma cell line turned out to be the cellular counterparts of the genes carried by the Harvey and Kirsten sarcoma viruses ³. A rat virus had been carrying a stolen human gene.

One gene makes two proteins. Exon 4 comes in two versions, giving KRAS4A and KRAS4B, which differ only in the tail that holds them to the membrane. KRAS4B, the dominant form, carries a run of lysines and a farnesyl group; KRAS4A carries a palmitate as well as a polybasic stretch, so either can anchor it ¹⁴. KRAS4A was long treated as a minor variant, until it was found in all 30 cancer cell lines tested, and at levels equal to KRAS4B in 17 colorectal tumours ¹⁴. Every common activating mutation sits in exon 1 or 2, so it damages both forms at once ¹².

A switch, and how it jams

KRAS is a switch. It is on when it holds GTP and off when it holds GDP, and the difference is a small movement in two loops, switch I and switch II, that close over the third phosphate when it is there and relax when it is gone. Effector proteins recognise the closed form ¹. Where exactly those loops begin and end depends on who is drawing them: switch II has been said to start anywhere between residues 58 and 60 and to end anywhere between 67 and 76. The map above uses one published set, residues 30 to 40 and 58 to 72, with the phosphate-binding loop at 10 to 14 ¹⁷.

On its own, KRAS is bad at both halves of the cycle. It cuts GTP slowly, so a GTPase-activating protein speeds that step up by orders of magnitude, and it lets go of GDP slowly, so an exchange factor does the same in the other direction. Because the protein binds the two nucleotides about equally well, and the cell holds roughly ten times more GTP than GDP, releasing GDP is enough to switch it on ¹.

The structure of Ras bound to its GAP showed what the cancer mutations break. The GAP pushes an arginine into the active site to stabilise the charge building up in the transition state, and holds switch II so that glutamine 61 can position the attacking water. Glycine 12 lies within van der Waals distance of both. The authors noted that even changing it to alanine, the smallest substitute, would disturb the arrangement ¹⁵.

That is why the mutations cluster where they do, and why they are not all the same. Codon 12 mutants slow hydrolysis, their own and the GAP-assisted kind, without changing exchange. Codon 13 mutants do that and also exchange nucleotide about ten times faster on their own. Glutamine 61 mutants have the lowest hydrolysis rates of all. Alanine 146 mutants leave hydrolysis alone and raise exchange a thousandfold ¹². A switch can be jammed on by breaking the off, or by flooding the on.

What it switches on

Active KRAS binds more than twenty proteins from ten families ⁵. Two routes out matter most in cancer. Down one, RAF phosphorylates MEK, MEK phosphorylates ERK, and ERK changes what the nucleus transcribes. Down the other, PI3K leads to AKT and mTORC1 ¹.

The cell does not leave this running. ERK acts back on SOS1 and on the receptors, damping the signal, which means blocking one step can release a brake elsewhere and is a large part of why single drugs stop working.

KRAS also has to be in the right place. Its tail is farnesylated, trimmed and methylated, and KRAS4B's lysines hold it against the negatively charged inner membrane. A chaperone, PDEδ, ferries it between membranes, and calmodulin can pull KRAS4B off the membrane altogether ¹. Position matters as much as shape: concentrating proteins onto a two-dimensional surface is worth about five orders of magnitude in binding ¹.

The drawing is a simplification in three ways. Each box is a family, not a protein: three RAF genes, two MEK genes, two ERK genes. There is feedback, with ERK acting back on SOS1 and on the receptors, so blocking one step can lift a brake somewhere else. And the two roads talk to each other.

That feedback is why SHP2, the phosphatase encoded by PTPN11, matters here. SHP2 inhibitors work in cancers whose RAS still cycles between GDP and GTP, including KRAS G12C, by cutting off SOS1-driven GTP loading ¹⁸. It is also why the colorectal combinations exist: blocking EGFR at the top of the pathway while a drug holds KRAS shut below ^19,20.

In cancer

Across 426,706 tumour samples, KRAS was the most frequently altered oncogene, changed in 23%: 88% of those were mutations, the rest amplification or both ⁴. Counting all three RAS genes and weighting by how common each cancer actually is, about 19% of cancer patients carry a RAS mutation, which works out at roughly 3.4 million new cases a year worldwide; KRAS accounts for three-quarters of them ⁵.

The mutation is not spread evenly. It is in 92% of pancreatic ductal adenocarcinomas, about half of colorectal cancers, a third of non-squamous lung cancers, and 2.1% of breast cancers ⁴. Three cancers, colorectal, lung and pancreatic, account for 71% of all KRAS-mutant disease ⁴.

Which mutation also depends on the cancer. G12C is 40% of KRAS-mutant non-squamous lung cancer, and it comes from the particular kind of DNA damage tobacco smoke causes ^4,12. G12D leads in pancreatic and endometrial cancer; codon 13 and codon 146 mutations are concentrated in the bowel ^4,12.

Different alleles behave differently in the clinic as well as the test tube, though the evidence is retrospective and inconsistent. In pancreatic cancer, G12D has been associated with worse survival and G12R with better; in colorectal cancer, codon 12 mutations with worse survival than codon 13 ¹². And what sits next to the KRAS mutation can matter more than the mutation: STK11, KEAP1 and TP53 define lung subsets with different biology and different responses ²¹.

Testing for it

For most of the time KRAS has been tested, the result could not be acted on except by subtraction. Two trials settled that in 2008: panitumumab improved progression-free survival only in patients whose colorectal tumours had wild-type KRAS ²², and cetuximab improved survival only in wild-type disease, 9.5 months against 4.8, while doing nothing at all in mutants ²³. The exclusion later widened to codons 59, 61, 117 and 146, in NRAS as well as KRAS ¹².

Today KRAS is read as part of a panel. Guidelines expect laboratories running next-generation sequencing on lung adenocarcinoma to report it among a defined set of genes ²⁴. The panel matters as much as the gene, because co-mutations in STK11, KEAP1 and TP53 change what to expect ²¹.

Blood can stand in for tissue. Across 62,369 liquid biopsies the pattern of KRAS variants matched tissue closely ⁴. But a joint ASCO and College of American Pathologists review found results that disagree with tissue genotyping, advised confirming an undetected result on tissue, and found no evidence of usefulness in early-stage disease, treatment monitoring or residual disease ²⁵.

• Tumour tissue sequencingKRAS is among the genes molecular testing guidelines expect a laboratory to report in lung adenocarcinoma when it runs a next-generation sequencing panel ²⁴.To choose a targeted drug, and in colorectal cancer to decide against one: a RAS mutation predicts no benefit from anti-EGFR antibodies ^22,23.Comprehensive profiling found KRAS alterations in 23% of 426,706 samples, 88% of them mutations ⁴.A needle samples a fraction of a tumour, and pancreatic samples are diluted by non-cancerous stroma, which is why database figures for pancreatic cancer run below the 88 to 92% that careful series report ^4,5.
• Circulating tumour DNATumour DNA in blood, used when tissue is not available or at progression ²⁵.In 62,369 liquid biopsies, the distribution of KRAS variants matched tissue closely ⁴.A joint ASCO and CAP review found results discordant with tissue genotyping and recommended confirming a negative blood result on tissue; it found no evidence of clinical utility in early-stage disease or monitoring ²⁵.

Drugging the undruggable

For thirty years KRAS was the standing example of an undruggable target. It holds its nucleotide with picomolar affinity, so nothing can compete for that site, and the rest of the surface is smooth ⁶. The first serious attempt went around it: block the enzyme that attaches the lipid anchor, and KRAS never reaches the membrane. It failed, because when farnesyltransferase is blocked, K-Ras and N-Ras simply accept a geranylgeranyl group instead ²⁶.

The way in came in 2013, and it was mutation-specific. The G12C mutation puts a cysteine next to the nucleotide site, and a compound can be built to bind it covalently, so it never touches the normal protein. The crystal structures showed something nobody had seen: a pocket beneath switch II that only exists when the compound is in it. Binding disrupts both switches, tips the protein's preference back towards GDP, and spoils its grip on RAF ⁶.

There was an objection, and the answer to it is the most interesting part. If oncogenic KRAS is permanently on, a drug that binds the off state should be useless. It is not, because G12C still cycles: it has a relatively brisk intrinsic GTPase, with a half-life around 25 minutes, and drug-bound protein is invisible to exchange factors, so each round of hydrolysis moves more of it into the trap ^1,27.

AMG 510, now sotorasib, was the first into the clinic ⁷. In mice it did something the biochemistry had not predicted: in animals with working immune systems it changed the tumour environment, cured some outright in combination with checkpoint blockade, and the cured mice then rejected a fresh tumour of the same kind ⁷. Sotorasib and adagrasib are now approved for previously treated G12C lung cancer ²⁸, with modest but real gains over chemotherapy: progression-free survival of 5.6 against 4.5 months, and 5.5 against 3.8 ^29,30.

Colorectal cancer needed a second drug. Responses to a G12C inhibitor alone were poor, because blocking KRAS lifts a brake on EGFR above it; adding an anti-EGFR antibody raised the response rate from 19% to 46% with adagrasib ²⁰, and sotorasib with panitumumab beat standard care in a randomised trial ¹⁹. That approval has been criticised for resting on progression-free survival without a demonstrated survival benefit ³¹.

The field has since moved past G12C in two directions. One targets other alleles: MRTX1133 binds G12D non-covalently with about 700-fold selectivity ³², and setidegrasib destroys G12D rather than blocking it ³³. The other stops avoiding the active state. Daraxonrasib forms a three-part complex with cyclophilin A and GTP-bound RAS, mutant and normal alike, and in 500 previously treated pancreatic cancer patients it roughly doubled median survival, from 6.7 to 13.2 months ³⁴; it was approved in August 2026 ³⁵. For a cancer where progress has come in weeks, that is a large step, with the usual cautions about short follow-up ³⁵.

How tumours escape

Resistance arrives, usually within a year. When 38 patients whose cancers progressed on adagrasib were sequenced before and after, mechanisms were found in 17 of them, and seven had more than one at once ⁴⁷.

Some tumours change KRAS again: new mutations at G12, G13, Q61, R68, H95 and Y96, or simply more copies of the mutant gene. Others take a different road entirely, with MET amplification, mutations in NRAS, BRAF, MAP2K1 or RET, fusions, or loss of NF1 or PTEN. In two of nine lung adenocarcinomas with paired biopsies the tumour came back as a squamous cancer, with no genetic mechanism found at all ⁴⁷. In more than half of the patients, nothing was found.

One mechanism is specific to how the first drugs work. Because they bind the off state, anything that keeps more KRAS loaded with GTP blunts them. Models resistant through KRAS amplification or an NRAS mutation responded to inhibitors that bind the active state instead ^48,49, which is the rationale for the RAS(ON) drugs now in trials ⁴⁶. Daraxonrasib has its own resistance pattern, including mutations in cyclophilin A, the chaperone it borrows ⁵⁰.

When it is inherited

The same gene causes a different kind of disease when the mutation is inherited. Germline KRAS variants cause Noonan syndrome and cardiofaciocutaneous syndrome, part of a group called the RASopathies, which also includes neurofibromatosis type 1 and Costello syndrome, and which all come from too much signalling through RAS–MAPK ^10,11,51. Noonan syndrome brings distinctive facial features, short stature, congenital heart disease, developmental delay, lymphatic malformations and bleeding problems ⁵².

The mutations are not the cancer ones. Germline KRAS and NRAS variants are rarely found at codons 12, 13 or 61 ¹³: those changes are too strong to survive development. The Noonan variants V14I, T58I and D153V hydrolyse GTP poorly and respond badly to GAPs, but less drastically so ¹⁰. Children with RASopathies are predisposed to leukaemia, and juvenile myelomonocytic leukaemia is driven by germline or somatic mutations in five genes of the same pathway, KRAS among them ⁵³.

What is strange about it

The gene is named after a rat virus, which had picked up a mouse gene, which turned out to be a human gene that causes human cancer ^2,3.

Losing KRAS entirely is lethal before birth in mice, while losing either of its two close relatives is not ^8,9. The gene that drives a fifth of human cancers is also the one the embryo cannot do without.

The drugs that work bind the off state of a protein whose whole problem is that it is stuck on. They work because stuck on is a statistical description, not an absolute one: the protein still cycles, and each cycle offers another chance to trap it ²⁷.

Where it connects

Sources

55 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.

1. 1
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   The switch, its regulators, the membrane and the lipid tail.

2. 2
   Kirsten WH, Mayer LA. Morphologic responses to a murine erythroblastosis virus.J Natl Cancer Inst · 1967 · 39(2):311–335PMID 18623947

   The virus the gene is named after.

3. 3
   Der CJ, Krontiris TG, Cooper GM. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses.Proc Natl Acad Sci U S A · 1982 · 79(11):3637–3640doi:10.1073/pnas.79.11.3637 · PMID 6285355

   The human oncogene identified.

4. 4
   Lee JK, Sivakumar S, Schrock AB, et al. Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.NPJ Precis Oncol · 2022 · 6(1):91doi:10.1038/s41698-022-00334-z · PMID 36494601

   426,706 adult samples; the frequency and allele figures used here.

5. 5
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   Cross-referenced databases weighted by cancer incidence.

6. 6
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   The switch-II pocket and the first covalent G12C compounds.

7. 7
   Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.Nature · 2019 · 575(7781):217–223doi:10.1038/s41586-019-1694-1 · PMID 31666701

   Sotorasib in preclinical models; immune effects.

8. 8
   Johnson L, Greenbaum D, Cichowski K, et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras.Genes Dev · 1997 · 11(19):2468–2481doi:10.1101/gad.11.19.2468 · PMID 9334313

   Embryonic lethality.

9. 9
   Koera K, Nakamura K, Nakao K, et al. K-ras is essential for the development of the mouse embryo.Oncogene · 1997 · 15(10):1151–1159doi:10.1038/sj.onc.1201284 · PMID 9294608

   Confirms the same, independently.

10. 10
    Schubbert S, Zenker M, Rowe SL, et al. Germline KRAS mutations cause Noonan syndrome.Nat Genet · 2006 · 38(3):331–336doi:10.1038/ng1748 · PMID 16474405

    V14I, T58I, D153V; defective hydrolysis and GAP response.

11. 11
    Niihori T, Aoki Y, Narumi Y, et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.Nat Genet · 2006 · 38(3):294–296doi:10.1038/ng1749 · PMID 16474404

    KRAS in 3 of 43; BRAF in 16.

12. 12
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    Allele-by-allele biochemistry, epidemiology and the anti-EGFR exclusion.

13. 13
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    Why germline variants avoid the cancer codons.

14. 14
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    KRAS4A is not a minor variant.

15. 15
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    The arginine finger, and why glycine 12 cannot be anything else.

16. 16
    Johnson CW, Lin YJ, Reid D, et al. Isoform-specific destabilization of the active site reveals a molecular mechanism of intrinsic activation of KRas G13D.Cell Rep · 2019 · 28(6):1538–1550.e7doi:10.1016/j.celrep.2019.07.026 · PMID 31390567

    Crystal structures of G13D; G13D as a quarter of colorectal KRAS mutations.

17. 17
    Pantsar T. The current understanding of KRAS protein structure and dynamics.Comput Struct Biotechnol J · 2020 · 18:189–198doi:10.1016/j.csbj.2019.12.004 · PMID 31988705

    The residue boundaries drawn in the domain map, and how much they vary between papers.

18. 18
    Nichols RJ, Haderk F, Stahlhut C, et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers.Nat Cell Biol · 2018 · 20(9):1064–1073doi:10.1038/s41556-018-0169-1 · PMID 30104724

    SHP2 inhibition cuts SOS1-driven GTP loading.

19. 19
    Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C.N Engl J Med · 2023 · 389(23):2125–2139doi:10.1056/NEJMoa2308795 · PMID 37870968

    CodeBreaK 300; manufacturer-funded.

20. 20
    Yaeger R, Weiss J, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C.N Engl J Med · 2023 · 388(1):44–54doi:10.1056/NEJMoa2212419 · PMID 36546659

    KRYSTAL-1 colorectal cohort; non-randomised.

21. 21
    Skoulidis F, Byers LA, Diao L, et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.Cancer Discov · 2015 · 5(8):860–877doi:10.1158/2159-8290.CD-14-1236 · PMID 26069186

    The KL, KP and KC subsets.

22. 22
    Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol · 2008 · 26(10):1626–1634doi:10.1200/JCO.2007.14.7116 · PMID 18316791

    427 patients; the first use of KRAS as a selection marker.

23. 23
    Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer.N Engl J Med · 2008 · 359(17):1757–1765doi:10.1056/NEJMoa0804385 · PMID 18946061

    394 patients; benefit confined to wild-type.

24. 24
    Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors.J Mol Diagn · 2018 · 20(2):129–159doi:10.1016/j.jmoldx.2017.11.004 · PMID 29398453

    KRAS among the genes expected on a sequencing panel.

25. 25
    Merker JD, Oxnard GR, Compton C, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review.J Clin Oncol · 2018 · 36(16):1631–1641doi:10.1200/JCO.2017.76.8671 · PMID 29504847

    What liquid biopsy can and cannot do.

26. 26
    Whyte DB, Kirschmeier P, Hockenberry TN, et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors.J Biol Chem · 1997 · 272(22):14459–14464doi:10.1074/jbc.272.22.14459 · PMID 9162087

    Why farnesyltransferase inhibitors failed for KRAS.

27. 27
    Lito P, Solomon M, Li LS, et al. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism.Science · 2016 · 351(6273):604–608doi:10.1126/science.aad6204 · PMID 26841430

    Why an off-state drug works on a protein that is supposedly always on.

28. 28
    Kasper S, Sebastian M. The pharmacologic inhibition of KRAS mutants as a treatment for cancer: therapeutic principles and clinical results.Dtsch Arztebl Int · 2025 · 122(6):163–167doi:10.3238/arztebl.m2025.0002 · PMID 40009739

    Review of approved use and the phase 3 numbers.

29. 29
    de Langen AJ, Johnson ML, Mazieres J, et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS G12C mutation: a randomised, open-label, phase 3 trial.Lancet · 2023 · 401(10378):733–746doi:10.1016/S0140-6736(23)00221-0 · PMID 36764316

    CodeBreaK 200; 345 patients; manufacturer-funded.

30. 30
    Barlesi F, Yao W, Duruisseaux M, et al. Adagrasib versus docetaxel in KRAS G12C-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial.Lancet · 2025 · 406(10503):615–626doi:10.1016/S0140-6736(25)00866-9 · PMID 40783289

    453 patients; manufacturer-funded.

31. 31
    Stevens SX, Gyawali B. CodeBreaK or code blue? Assessing sotorasib's vital signs in metastatic colorectal cancer.Cancer · 2025 · 131(17):e70056doi:10.1002/cncr.70056 · PMID 40831024

    No survival benefit established; criticism of trial design and reporting.

32. 32
    Hallin J, Bowcut V, Calinisan A, et al. Anti-tumor efficacy of a potent and selective non-covalent KRAS G12D inhibitor.Nat Med · 2022 · 28(10):2171–2182doi:10.1038/s41591-022-02007-7 · PMID 36216931

    MRTX1133; preclinical.

33. 33
    Park W, Kasi A, Spira AI, et al. Setidegrasib in advanced non-small-cell lung cancer and pancreatic cancer.N Engl J Med · 2026 · 394(14):1409–1420doi:10.1056/NEJMoa2600752 · PMID 41879829

    Phase 1 of a G12D degrader; manufacturer-funded.

34. 34
    O'Reilly EM, Wainberg ZA, Hendifar AE, et al. Daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer.N Engl J Med · 2026 · 395(4):325–337doi:10.1056/NEJMoa2605555 · PMID 42223072

    RASolute 302; 500 patients; manufacturer-funded.

35. 35
    Sun Y, Pang C, Gao J. Daraxonrasib: the first-in-class RAS(ON) multi-selective inhibitor approved for treatment of metastatic pancreatic adenocarcinoma.Drug Discov Ther · 2026 · advance onlinedoi:10.5582/ddt.2026.01067 · PMID 42802048

    The approval, the mechanism, and the cautions.

36. 36
    Ratain MJ, Fojo AT. Opportunities for harmonization of US Food and Drug Administration regulatory decisions exemplified by the traditional approval of sotorasib and panitumumab for colorectal cancer.J Clin Oncol · 2026 · 44(2):81–85doi:10.1200/JCO-25-01607 · PMID 41348990

    The full approval, and a commentary on how it was reached.

37. 37
    Matsumura N, Mandai M. PMDA regulatory update on approval and revision of the precautions for use of anticancer drugs in Japan.Int J Clin Oncol · 2025 · 30(12):2387–2388doi:10.1007/s10147-025-02901-3 · PMID 41138032

    Japanese approval of panitumumab with sotorasib.

38. 38
    Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation.N Engl J Med · 2021 · 384(25):2371–2381doi:10.1056/NEJMoa2103695 · PMID 34096690

    CodeBreaK 100 phase 2; manufacturer-funded.

39. 39
    Haddad SF, Bouferraa Y, Nair KG. Adagrasib in the treatment of colorectal cancer.Future Oncol · 2025 · 21(18):2275–2285doi:10.1080/14796694.2025.2524311 · PMID 40619745

    US accelerated approval 2024; not approved in the EU.

40. 40
    Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a KRAS G12C mutation.N Engl J Med · 2022 · 387(2):120–131doi:10.1056/NEJMoa2204619 · PMID 35658005

    KRYSTAL-1; manufacturer-funded.

41. 41
    Lamb YN. Fulzerasib: first approval.Drugs · 2024 · 84(12):1665–1671doi:10.1007/s40265-024-02120-6 · PMID 39587006

    Conditional approval in China, August 2024.

42. 42
    Gregorc V, Majem M, Lo Russo G, et al. Fulzerasib plus cetuximab in first-line KRAS G12C-mutated non-small-cell lung cancer (KROCUS): a single-arm, multicentre, phase 1b/2 trial.Lancet Oncol · 2026 · 27(4):432–441doi:10.1016/S1470-2045(25)00764-8 · PMID 41926959

    47 patients, single-arm; manufacturer-funded.

43. 43
    Li Z, Dang X, Huang D, et al. Garsorasib in patients with KRAS G12C-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 2 trial.Lancet Respir Med · 2024 · 12(8):589–598doi:10.1016/S2213-2600(24)00110-3 · PMID 38870979

    123 patients; single-arm.

44. 44
    Zhong J, Zhao J, Duan J, et al. Glecirasib plus sitneprotafib in patients with KRAS G12C-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 1/2a trial.Lancet Respir Med · 2026 · 14(2):163–173doi:10.1016/S2213-2600(25)00258-9 · PMID 41325755

    A G12C inhibitor paired with a SHP2 inhibitor.

45. 45
    Arbour KC, Punekar S, Luo J, et al. Daraxonrasib for previously treated RAS-mutant non-small-cell lung cancer.N Engl J Med · 2026 · 395(9):882–893doi:10.1056/NEJMoa2504059 · PMID 42685317

    136 patients, dose-finding; manufacturer-funded.

46. 46
    Cregg J, Pota K, Tomlinson ACA, et al. Discovery of elironrasib (RMC-6291), a potent and orally bioavailable, RAS(ON) G12C-selective, covalent tri-complex inhibitor.J Med Chem · 2025 · 68(6):6041–6063doi:10.1021/acs.jmedchem.4c02313 · PMID 39993169

    Active-state G12C inhibition; phase 1.

47. 47
    Awad MM, Liu S, Rybkin II, et al. Acquired resistance to KRAS G12C inhibition in cancer.N Engl J Med · 2021 · 384(25):2382–2393doi:10.1056/NEJMoa2105281 · PMID 34161704

    38 patients sequenced before and after progression.

48. 48
    Solanki HS, Shah H, Imbody D, et al. RAS-GTP inhibition overcomes acquired resistance to KRAS G12C inhibitors mediated by oncogenic and wild-type RAS activation in non-small cell lung cancer.Cancer Res · 2026 · 86(2):467–484doi:10.1158/0008-5472.CAN-25-0600 · PMID 41165456

    Resistance models; preclinical.

49. 49
    Nokin MJ, Mira A, Patrucco E, et al. RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade.Nat Commun · 2024 · 15(1):7554doi:10.1038/s41467-024-51828-2 · PMID 39215000

    Increased GTP loading as a resistance mechanism.

50. 50
    Lou J, Zhang D. Daraxonrasib and the era of pan-RAS inhibition: mechanisms, clinical advances, and resistance landscapes.Exp Hematol Oncol · 2026 · 15(1)doi:10.1186/s40164-026-00833-w · PMID 42806361

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