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Cited by 164Protein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysProtein Tyrosine Phosphatases

Drugging KRAS: Current perspectives and state-of-art review

Open access
Parikh, Kaushal, Banna, Giuseppe, Liu, Stephen V., Friedlaender, Alex, Desai, Aakash, Subbiah, Vivek, Addeo, Alfredo·2022·Journal of Hematology & Oncology
DOI 10.1186/s13045-022-01375-4PMC PMC9597994
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Abstract

After decades of efforts, we have recently made progress into targeting KRAS mutations in several malignancies. Known as the ‘holy grail’ of targeted cancer therapies, KRAS is the most frequently mutated oncogene in human malignancies. Under normal conditions, KRAS shuttles between the GDP-bound ‘off’ state and the GTP-bound ‘on’ state. Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis. In 2013, improved understanding of KRAS biology and newer drug designing technologies led to the crucial discovery of a cysteine drug-binding pocket in GDP-bound mutant KRAS G12C protein. Covalent inhibitors that block mutant KRAS G12C were successfully developed and sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline. Simultaneously, effects of KRAS mutations on tumour microenvironment were also discovered, partly owing to the universal use of immune checkpoint inhibitors. In this review, we discuss the discovery, biology, and function of KRAS in human malignancies. We also discuss the relationship between KRAS mutations and the tumour microenvironment, and therapeutic strategies to target KRAS. Finally, we review the current clinical evidence and ongoing clinical trials of novel agents targeting KRAS and shine light on resistance pathways known so far.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes KRAS biology, oncogenic mutations, tumor microenvironment effects, and therapeutic strategies, focusing on the clinical development of KRAS G12C inhibitors sotorasib and adagrasib. It highlights modest single-agent efficacy in NSCLC, tissue-specific differences, emerging resistance mechanisms, and investigational agents for non-G12C KRAS mutations.

Key findings

  • KRAS is the most frequently mutated oncogene in human malignancies, seen in 1 in 7 cancers; incidence is highest in pancreatic cancer (>85%), followed by colorectal cancer (~40%), NSCLC (~30%), and cholangiocarcinoma (~20%). G12C is the commonest KRAS mutation in NSCLC (~14% of lung adenocarcinomas), while G12D and G12V predominate in pancreatic and colorectal cancers.
  • In phase II CodeBreaK100, sotorasib 960 mg daily in KRAS G12C NSCLC (n=126) produced an ORR of 37.1%, median PFS of 6.8 months, and median OS of 12.5 months. Phase III CodeBreaK200 showed PFS of 5.6 vs 4.5 months with docetaxel (HR 0.66, 95% CI 0.51–0.86; p=0.002) but no OS benefit (10.6 vs 11.3 months; HR 1.01, 95% CI 0.77–1.33; p=0.53).
  • In phase II KRYSTAL-1, adagrasib 600 mg twice daily in KRAS G12C NSCLC (n=116) produced an ORR of 42.9%, median PFS of 6.5 months, and median OS of 12.6 months; intracranial confirmed ORR was 33.3% (95% CI 18.0–51.8) among 33 patients with previously treated, stable CNS metastases.
  • Acquired resistance to adagrasib monotherapy was identified in 45% of 38 patients; 88% of resistance mechanisms involved RAS-MAPK reactivation, including KRAS switch-II pocket mutations and alternate KRAS activating mutations. Co-mutations in STK11/KEAP1 reduced ORR to sotorasib and adagrasib (e.g., KEAP1-mut/STK11-wt ORR 14% and 14.3%, respectively).

Methods

  • Design: narrative review covering KRAS discovery, biology, signaling pathways, tumor microenvironment, and therapeutic targeting.
  • Data/sample: published literature, preclinical studies, and clinical trial data; includes a table of KRAS mutation incidence across aerodigestive malignancies extracted using cBioPortal.
  • Analysis: narrative synthesis of clinical evidence and ongoing trials; no systematic search strategy or meta-analytic methods are described.

Limitations

  • The paper does not explicitly state limitations of the review itself. It notes trial limitations: CodeBreaK200 was underpowered for OS and OS data were immature; some subgroup analyses had limited sample size (e.g., PD-L1 high n=9).
  • Evident from the text: this is a narrative review without a described systematic search strategy, inclusion criteria, or formal risk-of-bias assessment.
  • Evident from the text: conclusions rely heavily on single-arm phase I/II trials and preclinical data, with limited randomized phase III evidence at the time of writing.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s13045-022-01375-4

Cites

184 of 184 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 93 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    In the phase II portion of KRYSTAL-2, adagrasib 600 mg bid in 116 patients with KRAS G12C NSCLC produced an ORR of 42.9% with median follow-up 12.9 months.

    “The phase II portion of KRYSTAL-2 included 116 patients with KRAS G12C NSCLC treated with adagrasib 600 mg bid [100]. All patients had prior platinum-doublet chemotherapy and 98.3% had received both chemotherapy and checkpoint inhibitor therapy. With a median follow-up of 12.9 months, the ORR was 42.9%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Janne 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):120–31. source

      Not checked in the free run.

  • Findingnone given

    In phase 2 CodeBreaK100 and KRYSTAL-1 trials, less than 50% of patients achieved any objective response.

    “In the phase 2 CodeBreaK100 and KRYSTAL-1 trials, while a majority of patients achieved disease control, less than 50% achieved any objective response.”
    Quote in the paperSubstantial claim
  • Findingcitation

    In an analysis of 38 patients with KRAS G12C cancers treated with adagrasib monotherapy, mechanisms of acquired resistance were identified in 45%.

    “In an analysis of 38 patients with KRAS G12C cancers treated with adagrasib monotherapy, including 27 with NSCLC and 10 with colorectal cancer, mechanisms of acquired resistance were identified in 45% [113].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Awad MM, Liu S, Rybkin II, et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N Engl J Med. 2021;384(25):2382–93. source

      Not checked in the free run.

  • Findingcitation

    Biomarkers such as PD-L1 and TMB were not predictive or prognostic in patients with KRAS G12C-mutant NSCLC in CodeBreaK100.

    “Biomarkers such as PD-L1 and TMB, which have been studied to predict outcomes with immune checkpoint inhibitors, were not predictive or prognostic in patients with KRAS G12C-mutant NSCLC in CodeBreaK100 [104].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021;39(15):9003–9003. source

      Not checked in the free run.

  • Findingcitation

    KRAS G12C inhibitors sotorasib and adagrasib promote a pro-inflammatory microenvironment in murine models by increasing CD8+ T-cell infiltration and decreasing immunosuppressive cells.

    “KRAS G12C inhibitors sotorasib and adagrasib have shown to promote a pro-inflammatory microenvironment in murine models by increasing CD8 + T-cell infiltration and by decreasing immunosuppressive cells such as MDSCs, M2-polarized macrophages, Tregs and potentiate anti-PD1 antibody therapy [71, 161].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–23. source

      Not checked in the free run.

    • cites [161] Briere DM, Li S, Calinisan A, et al. The KRAS(G12C) inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy. Mol Cancer Ther. 2021;20(6):975–85. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 7
  • May combine two claims. 45

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    KRAS mutation incidence is highest in pancreatic cancers (>85%), followed by colorectal cancer (~40%), NSCLC (~30%) and cholangiocarcinoma (~20%).

    “Its incidence is highest in pancreatic cancers (> 85%) followed by colorectal cancer (~ 40%), NSCLC (~ 30%) and cholangiocarcinoma (~ 20%) (Table 1, Fig. 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In CodeBreak100 phase II, ORR to sotorasib was 50% in STK11-mutated/KEAP1-wild-type, 23% when both KEAP1 and STK11 were mutated, and 14% when KEAP1 was mutated with wild-type STK11.

    “While ORR was 50% in those with mutated STK11 and wild-type KEAP1, it was only 23% when both KEAP1 and STK11 were mutated and 14% when KEAP1 was mutated with wild-type STK11 (Table 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371–81. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In 46 patients with KRAS G12C colorectal cancer, adagrasib had an ORR of 22% and a disease control rate of 87%.

    “In a report of 46 patients with KRAS G12C colorectal cancer, the ORR with adagrasib was an encouraging 22% with a disease control rate of 87% [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Weiss J, Yaeger RD, Johnson ML, et al. LBA6 KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2021;32:S1294. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Combination of adagrasib with cetuximab in 32 patients with KRAS G12C colorectal cancer had an ORR of 43% and a disease control rate of 100%.

    “A combination of adagrasib with cetuximab, an EGFR-directed monoclonal antibody, was explored in 32 patients with KRAS G12C colorectal cancer. The ORR with this combination was 43% with a disease control rate of 100% [102].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Weiss J, Yaeger RD, Johnson ML, et al. LBA6 KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2021;32:S1294. source

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    Premisecitation

    Codon 13 mutations can exhibit intermediate sensitivity to NF1-mediated hydrolysis while codons 12 and 61 mutations are insensitive to NF1-mediated hydrolysis.

    “Codon 13 mutations can exhibit intermediate sensitivity to NF1-mediated hydrolysis while codons 12 and 61 mutations are insensitive to NF1-mediated hydrolysis [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Rabara D, Tran TH, Dharmaiah S, et al. KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis. Proc Natl Acad Sci U S A. 2019;116(44):22122–31. source

      Not checked in the free run.

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    Premisecitation

    Historically, targeting KRAS mutations has been challenging; KRAS was deemed the undruggable gene.

    “Historically, targeting KRAS mutations has been challenging; it was deemed the “undruggable gene.””
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Kinsey CG, Camolotto SA, Boespflug AM, et al. Protective autophagy elicited by RAF–>MEK–>ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019;25(4):620–7. source

      Not checked in the free run.

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    Premisecitation

    KRAS mutations regulate the tumour microenvironment and alter tumour stroma, immune cell infiltration and cytokine expression.

    “KRAS mutations regulate the tumour microenvironment and alter tumour stroma, immune cell infiltration and cytokine expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Hamarsheh S, Gross O, Brummer T, Zeiser R. Immune modulatory effects of oncogenic KRAS in cancer. Nat Commun. 2020;11(1):5439. source

      Not checked in the free run.

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    Premisecitation

    G12A, G13D and Q61L mutations have high affinity to RAF and favorably activate the MAPK pathway.

    “G12A, G13D and Q61L mutations have a high affinity to RAF and favorably activate the MAPK pathway [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol Cancer Res. 2015;13(9):1325–35. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    KRAS G12R point mutation was first identified in 1984 in tumour tissue of a 66-year-old man with squamous cell lung carcinoma.

    “In 1984, an activating KRAS G12R point mutation was first identified in the tumour tissue of a 66-year-old man with squamous cell lung carcinoma, which was not present in normal parenchymal or lymphocytes [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Santos E, Martin-Zanca D, Reddy EP, Pierotti MA, Della Porta G, Barbacid M. Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science. 1984;223(4637):661–4. source

      Not checked in the free run.

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    Premisecitation

    In pancreatic cancer, KRAS mutation is often the initiating genetic event leading to pancreatic intraepithelial neoplasms; other mutations include p53 (64%), SMAD4 (21%), and CDKN2A (17%).

    “In pancreatic cancer, KRAS mutation is often the initiating genetic event leading to pancreatic intraepithelial neoplasms. Carcinogenesis and metastasis are stimulated by acquiring other mutations such as p53 (64%), SMAD4 (21%), and CDKN2A (17%) [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Waters AM, Der CJ. KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb Perspect Med. 2018;8(9):a031435. source

      Not checked in the free run.

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    Premisecitation

    Median OS for KRAS-mutant NSCLC was 21 months whereas it was 12 months for KRAS/STK11 double-mutant NSCLC (HR 1.7, 95% CI 1.1-2.4, p = 0.002).

    “In one study, median OS for KRAS-mutant NSCLC was 21 months whereas it was 12 months for KRAS/STK11 double-mutant NSCLC (HR 1.7, 95% CI 1.1–2.4, p = 0.002) [56].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Arbour KC, Jordan E, Kim HR, et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin Cancer Res. 2018;24(2):334–40. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In pancreatic cancers, KRAS G12D and G12V are the predominant mutations, at 40% and 32% of all KRAS mutations, respectively, while G12R accounts for nearly 17%.

    “In pancreatic cancers, KRAS G12D and G12V are the predominant mutations, at 40% and 32% of all KRAS mutations, respectively, while G12R mutation accounts for nearly 17% of all KRAS mutations in pancreatic cancer [50].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Luo J. KRAS mutation in pancreatic cancer. Semin Oncol. 2021;48(1):10–8. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    KRAS-2 gene is located on the short arm of chromosome 12 (12p11.1-12p12.1).

    “KRAS-2 gene, located on the short arm of chromosome 12 (12p11.1-12p12.1) [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Popescu NC, Amsbaugh SC, DiPaolo JA, Tronick SR, Aaronson SA, Swan DC. Chromosomal localization of three human ras genes by in situ molecular hybridization. Somat Cell Mol Genet. 1985;11(2):149–55. source

      Not checked in the free run.

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    Premisecitation

    KRAS G12A, G12R, Q61H, and Q61L mutations have 40-80 fold decrease in intrinsic hydrolysis; G12V, G12D, and G13D have intermediate reduction.

    “KRAS G12A, G12R, Q61H, and Q61L mutations were found to have 40–80 fold decrease in intrinsic hydrolysis; G12V, G12D, and G13D mutations had an intermediate reduction in intrinsic hydrolysis [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol Cancer Res. 2015;13(9):1325–35. source

      Not checked in the free run.

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    Premisecitation

    Oncogenic KRAS mutations lead to decreased intrinsic GTPase activity and significantly increased resistance to GAP-mediated hydrolysis.

    “Oncogenic KRAS mutations lead to decreased intrinsic GTPase activity and significantly increased resistance to GAP-mediated hydrolysis [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Trahey M, McCormick F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science. 1987;238(4826):542–5. source

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    Premisecitation

    KRAS G12C is the commonest KRAS mutation in NSCLC, seen in about 14% of all lung adenocarcinomas, followed by G12V.

    “KRAS G12C is the commonest KRAS mutation in NSCLC, seen in about 14% of all lung adenocarcinomas, followed by G12V.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Dogan S, Shen R, Ang DC, et al. Molecular epidemiology of EGFR and KRAS mutations in 3026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res. 2012;18(22):6169–77. source

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    Premisecitation

    Among smokers, G12C is the commonest KRAS mutation (44%), followed by G12V (19%); G12D is the most frequent mutation in never-smokers (56%).

    “While G12C is the commonest KRAS mutation among smokers (44%), followed by G12V (19%), G12D is the most frequent mutation in never-smokers (56%) [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Dogan S, Shen R, Ang DC, et al. Molecular epidemiology of EGFR and KRAS mutations in 3026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res. 2012;18(22):6169–77. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis.

    “Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Trahey M, McCormick F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science. 1987;238(4826):542–5. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    KRAS mutations are seen in 1 in 7 of all human cancers.

    “KRAS is one of the most frequently mutated oncogenes in all human malignancies and is seen in 1 in 7 of all human cancers [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703–13. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mutations in codons 117 (K117N/R) and 146 (A146T/V) are seen exclusively in colon cancers.

    “Notably, mutations in codons 117 (K117N/R) and 146 (A146T/V) are seen exclusively in colon cancers [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Haigis KM. KRAS alleles: the devil is in the detail. Trends Cancer. 2017;3(10):686–97. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    KRAS G12C mutation was identified in 1984 in a human lung tumour (PR371) propagated in nude mice.

    “KRAS G12C mutation was identified in the same year in a human lung tumour (PR371) that was propagated in nude mice [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Nakano H, Yamamoto F, Neville C, Evans D, Mizuno T, Perucho M. Isolation of transforming sequences of two human lung carcinomas: structural and functional analysis of the activated c-K-ras oncogenes. Proc Natl Acad Sci U S A. 1984;81(1):71–5. source

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    Premisecitation

    Oncogenic KRAS mutations in codons 12, 13, and 61 inhibit GTP hydrolysis and prevent KRAS deactivation.

    “Oncogenic KRAS mutations in codons 12, 13, and 61 inhibit GTP hydrolysis and prevent KRAS deactivation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol Cancer Res. 2015;13(9):1325–35. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    G12C and G12V mutations preferentially activate RAL signaling and G12D-mutant cell lines have high levels of phosphorylated AKT, suggesting preferential activation of PI3K-AKT-mTOR pathway.

    “G12C and G12V mutations are shown to preferentially activate RAL signaling and G12D-mutant cell lines are shown to have high levels of phosphorylated AKT, suggesting preferential activation of PI3K-AKT-mTOR pathway [46, 47].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Ihle NT, Byers LA, Kim ES, et al. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst. 2012;104(3):228–39. source

      Not checked in the free run.

    • cites [47] Friedlaender A, Drilon A, Weiss GJ, Banna GL, Addeo A. KRAS as a druggable target in NSCLC: rising like a phoenix after decades of development failures. Cancer Treat Rev. 2020;85:101978. source

      Not checked in the free run.

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    Study design and conductcitation

    The OS data in CodeBreaK200 are not yet mature and the study was underpowered to show OS differences.

    “While the OS data are not yet mature and the study was underpowered to show OS differences, these results are disappointing and highlight the challenges with targeting KRAS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Johnson ML, de Langen AJ, Waterhouse DM, et al. LBA10 Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. Ann Oncol. 2022;33:S1417–8. source

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    Premisecitation

    In the 129 patients treated across dose levels in CodeBreaK100, treatment-related adverse events were observed in 56.6% and grade 3 or 4 TRAE in 11.6%.

    “In the 129 patients treated across dose levels, treatment-related adverse events (TRAE) were observed in 56.6% of patients but only 11.6% of patients experienced grade 3 or 4 TRAE.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Hong DS, Fakih MG, Strickler JH, et al. KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17. source

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  • May combine two claims.

    Premisecitation

    The switch II pocket was only seen in G12C-mutant protein, making it a target for drug development.

    “This switch II pocket was only seen in G12C-mutant protein, making it a target for drug development.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–51. source

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  • May combine two claims.

    Premisecitation

    Inhibition of KRAS G12C promotes an inflammatory TME by recruiting CD8+ T-cells and antigen presenting dendritic cells, and by increasing interferon signaling and chemokine production.

    “Inhibition of KRAS G12C was also shown to promote an inflammatory TME by recruiting CD8 + T-cells and antigen presenting dendritic cells, and by increasing interferon signaling and chemokine production [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–23. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With median follow-up of 11.7 months, response rate among patients with KRAS G12C NSCLC (n = 59) was 32.2% with disease control rate 88.1%.

    “With a median follow-up of 11.7 months, the response rate among patients with KRAS G12C NSCLC (n = 59) was 32.2% with a disease control rate of 88.1%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Hong DS, Fakih MG, Strickler JH, et al. KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17. source

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  • May combine two claims.

    Premisecitation

    Ostrem et al. developed multiple covalent inhibitors that bind to the cysteine residue at switch-II pocket of the KRAS-GDP complex, causing conformational change at switch I and switch II, preventing activation and downstream signaling, and inducing cell apoptosis.

    “Ostrem et al. developed multiple covalent inhibitors, which bind to the cysteine residue at switch-II pocket (S-IIP) of the KRAS-GDP complex. This leads to a conformational change at switch I and switch II regions, preventing its activation and downstream signaling, and eventually inducing cell apoptosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–51. source

      Not checked in the free run.

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    Premisecitation

    In KRYSTAL-1 phase I, median survival was not reached but the 12-month survival rate was 66.7%.

    “Median survival was not yet reached but the 12-month survival rate was 66.7%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Ou SI, Janne PA, Leal TA, et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRAS(G12C) solid tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530–38. source

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  • May combine two claims.

    Premisereasoning

    KRAS/STK11 co-mutations often have a CD8+ T-lymphocyte deficient and T-regulatory cell rich microenvironment whereas tumours with KRAS/p53 co-mutations have an inflamed tumour microenvironment rich in CD8+ T-lymphocytes.

    “KRAS/STK11 co-mutations often have a CD8 + T-lymphocyte deficient and T-regulatory cell rich microenvironment whereas tumours with KRAS/p53 co-mutations have an inflamed tumour microenvironment, rich in CD8 + T-lymphocytes [54, 56].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54] Bange E, Marmarelis ME, Hwang WT, et al. Impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy among patients with STK11-mutated advanced non-small-cell lung cancer. JCO Precis Oncol. 2019;3:PO.18.00326 source

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    • cites [56] Arbour KC, Jordan E, Kim HR, et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin Cancer Res. 2018;24(2):334–40. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In KRYSTAL-1 phase I, 15 evaluable patients with KRAS G12C NSCLC treated with adagrasib 600 mg bid had ORR 53.3%, median DOR 16.4 months, and median PFS 11.1 months.

    “There were 15 evaluable patients with KRAS G12C NSCLC treated with adagrasib 600 mg bid in the phase I portion of KRYSTAL-1. In this cohort, the ORR was 53.3% with a median duration of response of 16.4 months and a median PFS of 11.1 months.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Ou SI, Janne PA, Leal TA, et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRAS(G12C) solid tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530–38. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KRAS mutations activate YAP-TAZ and JAK-STAT pathways, leading to release of immunosuppressive cytokines such as CSF-1, IL-4, IL-6.

    “KRAS mutations activate Yes-associated protein-tafazzin (YAP-TAZ) and Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathways, leading to release of immunosuppressive cytokines such as CSF-1, IL-4, IL-6.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [65] Zhang W, Nandakumar N, Shi Y, et al. Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Sci Signal. 2014;7(324):ra42. source

      Not checked in the free run.

    • cites [66] Corcoran RB, Contino G, Deshpande V, et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 2011;71(14):5020–9. source

      Not checked in the free run.

    • cites [67] Gu M, Gao Y, Chang P. KRAS mutation dictates the cancer immune environment in pancreatic ductal adenocarcinoma and other adenocarcinomas. Cancers (Basel). 2021;13(10):2429. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Preclinical excitement with farnesyltransferase inhibitors did not translate to clinical utility with multiple negative phase II and phase III studies, likely due to presence of bypass prenylation pathway by geranylgeranylation.

    “However, preclinical excitement did not transcribe to clinical utility with multiple negative phase II and phase III studies, likely due to presence of bypass prenylation pathway by geranylgeranylation [79].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Zhang FL, Kirschmeier P, Carr D, et al. Characterization of Ha-ras, N-ras, Ki-Ras4A, and Ki-Ras4B as in vitro substrates for farnesyl protein transferase and geranylgeranyl protein transferase type I. J Biol Chem. 1997;272(15):10232–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ARS-853 was 600-fold more potent than compound 12 in engaging KRAS G12C and led to dose-dependent inhibition of SOS catalyzed nucleotide exchange and downstream MAPK signaling in KRAS G12C cells.

    “ARS-853 was found to be 600-fold more potent than compound 12 developed by Ostrem et al. in engaging KRAS G12C and led to a dose-dependent inhibition of SOS catalyzed nucleotide exchange and downstream MAPK signaling in KRAS G12C cells [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Patricelli MP, Janes MR, Li LS, et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 2016;6(3):316–29. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These covalent inhibitors did not block the GTP-bound state and require intrinsic GTPase hydrolysis of KRAS G12C to the GDP-bound state for activity.

    “Notably, these compounds did not block the GTP-bound state and require intrinsic GTPase hydrolysis of KRAS G12C to the GDP-bound state for activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–51. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In CodeBreaK100 phase II, sotorasib 960 mg once daily in KRAS G12C NSCLC cohort of 126 patients produced response rate 37.1% and disease control 80.6% with median follow-up 15.3 months.

    “The NSCLC cohort included 126 patients, 81% of whom had received prior platinum-based chemotherapy and PD(L)1 inhibitor therapy. With a median follow-up of 15.3 months, the response rate was 37.1%; 80.6% of patients achieved disease control.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371–81. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In NSCLC, KRAS G12D mutation is associated with lower tumour-mutation burden, decreased PDL1 expression, and reduced CD8+ T cell infiltration in the TME.

    “In NSCLC, KRAS G12D mutation has been associated with a lower tumour-mutation burden, decreased PDL1 expression, and reduced CD8 + T cell infiltration in the TME [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Ricciuti B, Alessi JV, Elkrief A, et al. Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRAS(G12D) mutated non-small cell lung cancer. Ann Oncol. 2022. https://doi.org/10.1016/j.annonc.2022.07.005. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Historically, targeting KRAS mutations had been unsuccessful due to high affinity to GTP, a smooth surface without a drug binding groove or pocket, and multiple resistance mechanisms.

    “The RAS molecule has a high affinity in picomolar range to abundantly available cytoplasmic GTP making competitive inhibition challenging.”
    • Also stated in: § Targeting KRAS mutations · plain
      “Secondly, unlike other molecules with a targeted inhibitor, the RAS protein has a smooth surface without expression of a drug binding groove or pocket.”
    • Also stated in: § Targeting KRAS mutations · plain
      “Lastly, RAS pathways have several upstream and downstream regulators, which allow for multiple resistance mechanisms and bypass signals to overcome inhibition [75].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] LoRusso PM, Sebolt-Leopold JS. One step at a time—clinical evidence that KRAS Is indeed druggable. N Engl J Med. 2020;383(13):1277–8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In KRYSTAL-1 phase I, no maximally tolerated dose was identified, though five patients had at least one dose limiting toxicity.

    “No maximally tolerated dose was identified, though five patients had at least one dose limiting toxicity; dose limiting toxicities included diarrhea, nausea, fatigue, amylase elevation, lipase elevation, and decreased appetite.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Ou SI, Janne PA, Leal TA, et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRAS(G12C) solid tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530–38. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In CodeBreaK100 phase I/II, no dose-limiting toxicities were encountered at planned dose levels of 180 mg, 360 mg, 720 mg, and 960 mg, with 960 mg established as recommended phase II dose.

    “In the phase I dose escalation portion, no dose-limiting toxicities were encountered at the planned dose levels of 180 mg, 360 mg, 720 mg, and 960 mg, with 960 mg established as the recommended phase II dose.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Hong DS, Fakih MG, Strickler JH, et al. KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    KRAS mutations independently, and in conjunction with other co-mutations, influence tumour growth, changes in tumour microenvironment, and the efficacy of immunotherapy.

    “In summary, KRAS mutations independently, and in conjunction with other co-mutations influence tumour growth, changes in tumour microenvironment, and the efficacy of immunotherapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Early clinical studies of KRAS G12C inhibitors showed responses across tumour types, but monotherapy was most effective in NSCLC.

    “Early clinical studies explored efficacy across tumour types and while responses were observed in different cancers, monotherapy was most effective in NSCLC.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CodeBreaK200 did not meet its secondary endpoint of OS; median OS was 10.6 months for sotorasib and 11.3 months for docetaxel (HR 1.01, 95% CI 0.77-1.33; p = 0.53).

    “However, the study did not meet its secondary endpoint of OS. Median OS was 10.6 months (95% CI 8.9–14.0) for sotorasib and 11.3 months (9.0–14.9) for docetaxel (HR 1.01, 95% CI 0.77–1.33; p = 0.53).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Johnson ML, de Langen AJ, Waterhouse DM, et al. LBA10 Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. Ann Oncol. 2022;33:S1417–8. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These CodeBreaK200 results are disappointing and highlight the challenges with targeting KRAS.

    “While the OS data are not yet mature and the study was underpowered to show OS differences, these results are disappointing and highlight the challenges with targeting KRAS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In CodeBreak100 phase II for KRAS G12C-mutant colorectal cancer, 62 patients had ORR 9.7%, disease control 82.3%, and median PFS 4.0 months.

    “The phase II portion of CodeBreak100 for KRAS G12C-mutant colorectal cancer included 62 patients with prior fluoropyrimidine, oxaliplatin, and irinotecan treatment [97]. The ORR was only 9.7% (n = 6), and though 82.3% achieved disease control, the overall median PFS was only 4.0 months.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Fakih MG, Kopetz S, Kuboki Y, et al. Sotorasib for previously treated colorectal cancers with KRAS(G12C) mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol. 2022;23(1):115–24. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sotorasib and adagrasib are orally bioavailable small molecules that selectively and irreversibly bind KRAS G12C in its GDP-bound state, locking it in its inactive conformation.

    “Both sotorasib and adagrasib are orally bioavailable small molecules that selectively and irreversibly bind KRAS G12C in its GDP-bound state, locking it in its inactive conformation (Fig. 5).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [93] Hong DS, Fakih MG, Strickler JH, et al. KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–17. source

      Not checked in the free run.

    • cites [99] Ou SI, Janne PA, Leal TA, et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRAS(G12C) solid tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530–38. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In CodeBreaK100 phase II, median PFS was 6.8 months and median survival was 12.5 months.

    “Median PFS was 6.8 months and median survival was 12.5 months (Table 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371–81. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A phase II study of tipifarnib in HRAS-mutant head and neck squamous cell carcinoma showed an objective response rate of 55%, PFS of 5.6 months, and median OS of 15.4 months.

    “A phase II study of tipifarnib in HRAS-mutant head and neck squamous cell carcinoma showed an objective response rate of 55%, PFS of 5.6 months, and median OS of 15.4 months [81].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Ho AL, Brana I, Haddad R, et al. Tipifarnib in head and neck squamous cell carcinoma with HRAS mutations. J Clin Oncol. 2021;39(17):1856–64. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CodeBreaK200 met its primary endpoint; PFS was 5.6 months with sotorasib and 4.5 months with docetaxel (HR 0.66, 95% CI 0.51-0.86; p = 0.002).

    “The trial met its primary endpoint and PFS was 5.6 months (95% CI 4.3–7.8) with sotorasib and 4.5 months (95% CI 3.0–5.7) with docetaxel (HR 0.66, 95% CI 0.51–0.86; p = 0.002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Johnson ML, de Langen AJ, Waterhouse DM, et al. LBA10 Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. Ann Oncol. 2022;33:S1417–8. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The 600 mg twice daily dose of adagrasib was recommended for phase II trials.

    “The 600 mg twice daily dose of adagrasib was recommended for phase II trials.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Ou SI, Janne PA, Leal TA, et al. First-in-human phase I/IB dose-finding study of adagrasib (MRTX849) in patients with advanced KRAS(G12C) solid tumors (KRYSTAL-1). J Clin Oncol. 2022;40(23):2530–38. source

      Not checked in the free run.

51 of 51

  • The paper relies on this without support.

    KRAS requires localization to the cell membrane for its activity and downstream signaling.

    “KRAS monomers require localization to the cell membrane for their activity.”
    “Since membrane localization of KRAS is essential for its downstream signaling, blocking it appeared a sound rationale for inhibition of mutant KRAS.”

  • The paper relies on this without support.

    Cysteine is the most reactive amino acid.

    “Cysteine is the most reactive amino acid, and experiences with agents such as ibrutinib and dacomitinib have shown that active cysteine acts as a nucleophile to form covalent bonds with these agents [85, 86].”

  • The paper relies on this without support.

    Preclinical findings in mouse models and cell lines are predictive of clinical efficacy and resistance in patients.

    “These results mirror those seen in preclinical mouse models; adagrasib has also demonstrated efficacy in intracranial xenograft mouse models.”

  • The paper relies on this without support.

    Immunotherapy and combination chemotherapy and immunotherapy remain the standard of care for patients with metastatic KRAS-mutant NSCLC.

    “As we await results of studies using KRAS inhibitors in the first line of treatment, immunotherapy and combination of chemotherapy and immunotherapy remain the standard of care for patients with metastatic KRAS-mutant NSCLC.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Sotorasib dose differs between text and tables

    Minor

    The phase II CodeBreaK100 dose is stated as 960 mg once daily, but the corresponding sotorasib rows in Tables 2 and 3 say 920 mg daily.

  • Two different enzymes are called the final MAPK enzyme

    Minor

    One section identifies ERK as the final enzyme in the MAPK pathway; another identifies cyclin D kinase as the final enzyme in that pathway.

  • Adagrasib phase II trial is named inconsistently

    Minor

    The phase II adagrasib cohort is called KRYSTAL-2 here, while the preceding text and Table 2 identify the phase I/II study as KRYSTAL-1.

  • Three resistance categories are followed by four

    Minor

    The sentence announces three categories of acquired resistance but enumerates four.

  • Harvey experiment describes rats in the text but mice in its cited title

    Minor

    The account attributes the 1964 observation to an experiment in rats, whereas the title of its cited reference describes tumour production in mice.

5 of 5

Cites

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1 of the 185 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Parikh, K., Banna, G., Liu, S. V., Friedlaender, A., Desai, A., Subbiah, V., & Addeo, A.
Affiliations
  • Mayo Clinic (US)
  • Portsmouth Hospitals NHS Trust (GB)
  • Georgetown University (US)
  • Générale-Beaulieu Clinic (CH)
  • The University of Texas MD Anderson Cancer Center (US)
  • University Hospital of Geneva (CH)
Corresponding author
Addeo, Alfredo
ORCID
Venue
Journal of Hematology & Oncology
Publisher
Springer Science and Business Media LLC
Published
2022-10-25
Volume
15
Issue
1
Pages
152-152
ISSN
1756-8722 (ISSN-L)
DOI
10.1186/s13045-022-01375-4
PMC
PMC9597994
OpenAlex
W4307201601
Semantic Scholar
f44178cad1b5f1242d8c8723585dce5e9fd545ed
Cited by
164
References
185
Citations by year
2026: 38 · 2025: 55 · 2024: 43 · 2023: 27 · 2022: 1
FWCI
3.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hematology & Oncology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
KRAS, KRAS G12C, KRAS inhibitors, sotorasib, covalent inhibitors, tumor microenvironment, immune checkpoint inhibitors, drug resistance, oncogenes, targeted cancer therapy, clinical trials
MeSH terms
Immune Checkpoint Inhibitors, Antineoplastic Agents, Cysteine, Guanosine Triphosphate, Humans, Mutation, Neoplasms, Proto-Oncogene Proteins p21(ras), Tumor Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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