Affinage

KRAS

GTPase KRas · UniProt P01116

Length
189 aa
Mass
21.7 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KRAS encodes a membrane-associated small GTPase that cycles between inactive GDP-bound and active GTP-bound states to drive RAF/MEK/ERK signaling, with oncogenic activation occurring when mutations at G12, G13, and Q61 disrupt the GAP arginine finger/Q61 catalytic organization required for GTP hydrolysis (PMID:26902995). The catalytic mutants are not uniformly GAP-insensitive: KRAS G13D retains susceptibility to neurofibromin (NF1)-stimulated hydrolysis, and KRAS G13D cells respond to EGFR inhibitors in an NF1-dependent manner (PMID:31611389). Plasma membrane targeting of K-Ras4B depends on C-terminal processing — FTase recognizes the CAAX motif and adjacent polybasic region with high specificity (PMID:10673434), though the protein can be alternatively geranylgeranylated when farnesylation is blocked, with oncogenic MAP kinase signaling sensitive to GGTase I inhibition (PMID:7592913). Membrane association is dynamic and reversible (PMID:16236799) and is governed by the hypervariable region, which mediates lipid binding (PMID:20566322), interacts with Ca2+-loaded calmodulin to extract K-Ras4B from the bilayer (PMID:19583261, PMID:27410739), and is phosphorylated at Ser181 by PKC (antagonized by calmodulin) to reduce p120GAP susceptibility, lower membrane affinity, and sustain ERK/AKT-driven proliferation and oncogenic function (PMID:20802526, PMID:28448716). KRAS can self-associate through a dimer interface, and the dimerization-defective KRAS D154Q mutant abrogates oncogenic activity and MEK-inhibitor resistance, establishing dimerization as required for KRAS function (PMID:29336889). Deep mutational scanning maps allosteric communication across the central β-sheet and identifies surface pockets that tune effector binding (PMID:38109937), and KRAS-dependent transcription in mutant cancers operates predominantly through ERK to deregulate the APC/C and cell cycle machinery driving PDAC growth (PMID:38843331). Counterbalancing its oncogenic role, wild-type Kras2 acts as a tumor suppressor that restrains ERK activity and inhibits tumors driven by activated Kras (PMID:11528387), and Kras is uniquely required among Ras genes for pre-BCR/BCR-driven Raf-1/MEK/ERK signaling in B cell development (PMID:26773157). KRAS is therapeutically targeted by switch I/II-pocket inhibitors (PMID:31332011), membrane-orientation-modulating compounds (PMID:30122370), and a KRAS G12D-selective VHL-recruiting degrader (PMID:40849515), but resistance arises through feedback reactivation of wild-type RAS via RTKs (PMID:35732135), SRC–JUN-driven ABCC1 expression (PMID:39661665), and CAF-derived NRG1 engagement of ERBB2/3 (PMID:37775182).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1995 Medium

    Established how K-Ras4B reaches the membrane and whether its prenylation could be pharmacologically intercepted, revealing it escapes FTase inhibition via alternative geranylgeranylation.

    Evidence Cell-based prenylation and MAP kinase activation assays with isoform-selective CAAX inhibitors

    PMID:7592913

    Open questions at the time
    • Does not establish in vivo relevance of GGTase I targeting in tumors
    • No structural basis for the differential inhibitor sensitivity
  2. 2000 High

    Defined the structural basis for K-Ras4B's high-affinity recognition by farnesyltransferase, explaining CAAX and polybasic-region specificity.

    Evidence X-ray crystallography of four FTase/K-Ras4B peptide ternary complexes at 2 Å

    PMID:10673434

    Open questions at the time
    • Peptide substrates rather than full-length protein
    • Does not address alternative prenylation enzymes
  3. 2001 High

    Demonstrated that wild-type Kras paradoxically acts as a tumor suppressor restraining ERK, reframing the gene as dual-function rather than purely oncogenic.

    Evidence Kras2-deficient mouse lung tumor bioassays, colony formation, xenograft, and ERK activity measurement

    PMID:11528387

    Open questions at the time
    • Molecular mechanism of WT suppression of mutant Kras not resolved here
    • Tissue specificity of the suppressor role unclear
  4. 2005 Medium

    Showed that K-Ras4B membrane binding is rapidly reversible rather than static, establishing dynamic membrane shuttling as a regulatory feature.

    Evidence Rapamycin-regulated heterodimerization and live-cell imaging of PM-to-mitochondria transfer

    PMID:16236799

    Open questions at the time
    • Physiological trigger for membrane release not defined
    • Single-cell imaging without endogenous-level confirmation
  5. 2009 High

    Identified calmodulin as a nucleotide-sensitive HVR-binding partner, providing a molecular handle for K-Ras4B regulation beyond GEFs/GAPs.

    Evidence NMR and ITC domain-mapping of HVR/calmodulin interaction

    PMID:19583261

    Open questions at the time
    • Cellular consequence of binding not tested in this study
    • Affinity measured on isolated domains
  6. 2010 Medium

    Connected PKC-mediated Ser181 phosphorylation (CaM-antagonized) to reduced GAP sensitivity and oncogenic output, defining a phospho-switch on the HVR.

    Evidence Cell-based phosphorylation and S181A mutant assays, p120GAP activity, proliferation and focus formation

    PMID:20802526

    Open questions at the time
    • Quantitative stoichiometry of phosphorylation in tumors unknown
    • Direct structural effect on GAP binding not shown
  7. 2010 Medium

    Confirmed that the HVR is the lipid-binding determinant, grounding membrane targeting in a defined region.

    Evidence Nanodisc reconstitution and NMR of recombinant K-Ras4B

    PMID:20566322

    Open questions at the time
    • Single method, no in-cell validation
    • Lipid composition dependence not explored
  8. 2012 Medium

    Revealed that synonymous rare-codon usage hardwires low KRAS protein levels, explaining the expression and tumorigenicity gap versus HRAS.

    Evidence Codon-optimized KRAS constructs with protein-level and tumorigenicity readouts

    PMID:23246410

    Open questions at the time
    • Translational mechanism (tRNA availability vs elongation) not dissected
    • Relevance to endogenous regulation in normal tissue unclear
  9. 2015 Medium

    Proposed nucleotide-gated self-association with distinct dimer interfaces controlling effector access, opening the question of whether KRAS dimerizes functionally.

    Evidence Structural modeling and biophysical characterization of GTP-bound K-Ras4B catalytic domain

    PMID:26051715

    Open questions at the time
    • No in-cell validation in this study
    • Catalytic domain only, lacks membrane context
  10. 2016 Low

    Provided an atomistic account of how G12/G13/Q61 mutations impair GAP-assisted hydrolysis and bias the active conformation.

    Evidence Microsecond molecular dynamics simulations of wild-type and mutant K-Ras4B ± GAP

    PMID:26902995

    Open questions at the time
    • Computational only, no experimental validation in this study
    • Does not capture full-length membrane-bound dynamics
  11. 2016 Medium

    Showed calmodulin physically extracts K-Ras4B from membranes nucleotide-independently, defining a sequestration mechanism distinct from PDEδ.

    Evidence FRET/FCS/imaging in model biomembranes with GDP/GTP-loaded K-Ras4B

    PMID:27410739

    Open questions at the time
    • In vitro model membranes only
    • Quantitative contribution to cellular PM pool not established
  12. 2016 High

    Established a unique, non-redundant requirement for Kras in B cell development via pre-BCR/BCR-driven MAPK signaling.

    Evidence Conditional Kras knockout mice and bone marrow chimeras with developmental and pathway analysis

    PMID:26773157

    Open questions at the time
    • Why other Ras genes cannot compensate is unresolved
    • Direct receptor-to-Kras coupling not biochemically mapped
  13. 2017 High

    Demonstrated with fully modified protein that Ser181 phosphorylation lowers membrane affinity while preserving PDEδ binding, integrating phospho-regulation with the shuttle machinery.

    Evidence Chemically synthesized phospho/farnesyl/methyl K-Ras4B, model membrane assays, cell microinjection

    PMID:28448716

    Open questions at the time
    • Downstream signaling consequences not quantified here
    • Endogenous phosphorylation dynamics not measured
  14. 2018 High

    Provided in vivo genetic proof that dimerization (D154Q-sensitive) is required for oncogenic KRAS activity and MEK-inhibitor resistance.

    Evidence Inducible KRAS LOH model, D154Q dimer-interface mutant, in vitro and in vivo tumor and MEKi assays

    PMID:29336889

    Open questions at the time
    • Stoichiometry and partner of dimerization in cells not fully defined
    • Apparent tension with native-protein in vitro non-dimerization findings
  15. 2018 Medium

    Rigorously tested intrinsic dimerization of natively processed K-Ras4B and found none on bilayers, implying cellular clustering needs accessory factors.

    Evidence FCS and single-molecule tracking of farnesylated/methylated K-Ras4B on supported lipid bilayers

    PMID:29320680

    Open questions at the time
    • Does not exclude dimerization driven by cellular factors
    • Single in vitro system
  16. 2018 Medium

    Showed that membrane orientation can occlude the effector site, identifying a druggable mode where a compound pins KRAS to the bilayer to block RAF.

    Evidence NMR of prenylated K-RAS4B in lipid bilayer plus RAF binding and signaling assays

    PMID:30122370

    Open questions at the time
    • Single compound, single lab
    • In-cell potency and selectivity limited
  17. 2019 High

    Resolved that KRAS G13D remains neurofibromin-sensitive, structurally and functionally rationalizing EGFR-inhibitor responsiveness for this allele.

    Evidence In vitro hydrolysis, KRAS G13D/NF1 crystal structure, NF1-dependent EGFR inhibitor cell assays

    PMID:31611389

    Open questions at the time
    • Generalizability to other codon-13 alleles untested
    • NF1 status dependence in patients not addressed
  18. 2019 High

    Validated the switch I/II pocket as a druggable site whose occupancy simultaneously blocks GEF, GAP, and effector engagement.

    Evidence Structure-based design of BI-2852 with binding, interaction-blockade, and proliferation assays

    PMID:31332011

    Open questions at the time
    • Potency insufficient for clinical use
    • Mutant selectivity not achieved
  19. 2022 Medium

    Distinguished the source of adaptive resistance to KRASG12C inhibition as feedback activation of wild-type RAS via RTKs rather than re-loading of mutant KRAS.

    Evidence Biochemical KRASG12C-GTP vs WT-RAS-GTP discrimination and RTK perturbation in NSCLC/CRC models

    PMID:35732135

    Open questions at the time
    • Identity of dominant upstream RTK varies by context
    • Single lab
  20. 2023 High

    Mapped genome-wide allosteric architecture of KRAS, identifying β-sheet-propagated communication and distal pockets that tune effector specificity.

    Evidence Deep mutational scanning of >26,000 variants against six partners with double-mutant free-energy inference

    PMID:38109937

    Open questions at the time
    • Druggability of identified distal pockets not demonstrated
    • Performed outside full membrane context
  21. 2023 Medium

    Identified a stromal bypass route in which CAF-derived NRG1 sustains KRAS-independent growth through ERBB2/3 upon KRAS extinction.

    Evidence Genetic/pharmacological KRAS, ERBB2/3, NRG1 perturbation and co-culture in PDAC models

    PMID:37775182

    Open questions at the time
    • Contribution relative to cell-intrinsic resistance unquantified
    • Single lab
  22. 2024 High

    Showed KRAS-mutant transcriptional output runs predominantly through ERK to deregulate the APC/C and cell cycle, defining the proliferative effector program.

    Evidence Genome-scale loss-of-function with integrated RNA-seq, phospho- and total proteomics in KRAS-mutant lines and patient data

    PMID:38843331

    Open questions at the time
    • Direct transcription factors linking ERK to APC/C not all defined
    • Tissue scope beyond PDAC partial
  23. 2024 High

    Defined an SRC–JUN–ABCC1 axis driving multidrug resistance to KRASG12C inhibition and a synergistic SRC-inhibitor combination strategy.

    Evidence Genome-wide CRISPR screen with pathway validation and SRC-inhibitor combinations across cells, organoids, and mice

    PMID:39661665

    Open questions at the time
    • Clinical translatability of the combination untested here
    • Whether axis generalizes to other KRAS alleles unknown
  24. 2025 High

    Delivered targeted KRASG12D protein degradation via a VHL-recruiting degrader, expanding KRAS therapeutics from inhibition to mutant-selective destruction.

    Evidence Ternary KRASG12D/ASP3082/VHL crystal structure, in vitro degradation, and xenograft regression

    PMID:40849515

    Open questions at the time
    • Resistance mechanisms to degradation not yet characterized
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the in vitro non-dimerizing behavior of natively processed K-Ras4B is reconciled with the genetic requirement for dimerization in cells — i.e., what cellular factors organize KRAS lateral assembly — remains unresolved.
  • Accessory factors driving cellular dimerization unidentified
  • Structural model of the cellular dimer in a membrane context missing
  • Quantitative link between dimerization and effector activation incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 2 GO:0008289 lipid binding 2 GO:0060089 molecular transducer activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-1266738 Developmental Biology 1 R-HSA-1640170 Cell Cycle 1
Partners
CALM1NF1PDE6DPRKCRAF1VHL

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 KRAS dimerization at the α4-α5 interface mediates wild-type KRAS-dependent growth inhibition of KRAS-mutant tumor cells and underlies resistance to MEK inhibition. The dimerization-defective mutant KRASD154Q abrogates these effects both in vitro and in vivo, establishing that dimerization is required for oncogenic KRAS activity. Genetically inducible KRAS LOH model, KRASD154Q dimer-interface mutant, in vitro and in vivo tumor growth assays, MEK inhibitor sensitivity assays Cell High 29336889
2015 GTP-bound K-Ras4B catalytic domain forms stable homodimers with two major dimer interfaces: a β-sheet interface overlapping switch I and effector-binding regions (inhibitory to effectors) and a helical interface that may promote Raf activation, suggesting Ras self-association regulates effector binding. Structural modeling, biophysical characterization of K-Ras4B GTP-bound catalytic domain dimerization Structure Medium 26051715
2018 Full-length, natively processed K-Ras4B (with farnesylation and methylation) lacks intrinsic dimerization capability on supported lipid bilayer membranes across a wide range of surface densities and lipid compositions, suggesting any lateral organization in living cells requires additional factors. Fluorescence correlation spectroscopy and single-molecule tracking in supported lipid bilayer membranes Biophysical journal Medium 29320680
2019 KRAS G13D mutant is sensitive to neurofibromin (NF1)-stimulated GTP hydrolysis. Crystal structures of KRAS G13D in complex with the NF1 RasGAP domain provide the structural basis for this hydrolysis, and KRAS G13D-mutated cells can respond to EGFR inhibitors in a neurofibromin-dependent manner. In vitro GTP hydrolysis assay, crystal structure determination of KRAS G13D/neurofibromin complex, cell-based EGFR inhibitor response assays with NF1 dependency Proceedings of the National Academy of Sciences of the United States of America High 31611389
2016 Oncogenic mutations at G12, G13, and Q61 in K-Ras4B impair GAP-assisted GTP hydrolysis by disrupting the R789 arginine finger / Q61 catalytic organization. G12C/G12D mutations additionally expose the bound nucleotide in the GDP state, facilitating GDP-to-GTP exchange. The mutations differentially drive an inactive-to-active conformational transition in the GTP-bound state. Molecular dynamics simulations (6.4 μs total) on wild-type and mutant K-Ras4B with and without GAP Scientific reports Low 26902995
2000 Crystal structures of four FTase ternary complexes with K-Ras4B peptide substrates reveal that the CAAX motif binds in extended conformation coordinating the active-site zinc ion, and the K-Ras4B polybasic region forms a type I β-turn along the rim of the hydrophobic cavity, providing the molecular basis for the high-affinity specificity of K-Ras4B for FTase. X-ray crystallography (2 Å resolution ternary complex structures) Structure High 10673434
1995 K-Ras4B processing (farnesylation) is highly resistant to FTI-277 (IC50 ~10 μM) but sensitive to the GGTase I inhibitor GGTI-286 (IC50 ~2 μM), demonstrating that K-Ras4B can undergo geranylgeranylation as an alternative prenylation when farnesylation is blocked, and that its oncogenic signaling (MAP kinase activation) is selectively disrupted by GGTase I inhibition. Cell-based prenylation processing assay, MAP kinase activation assay, CAAX peptidomimetic inhibitor treatment The Journal of biological chemistry Medium 7592913
2009 The C-terminal hypervariable region (HVR) of K-Ras4B is responsible for its specific interaction with calmodulin. The HVR binds specifically to the C-terminal domain of Ca2+-loaded calmodulin with micromolar affinity, while the GTP-γ-S-loaded catalytic domain may interact with the N-terminal domain of calmodulin, providing nucleotide-dependent control of the interaction. NMR spectroscopy and isothermal titration calorimetry Biochemistry High 19583261
2010 Calmodulin (CaM) inhibits K-Ras4B phosphorylation at Ser181 by PKC in vivo. PKC-mediated Ser181 phosphorylation decreases K-Ras4B susceptibility to p120GAP activity and is required for sustained ERK/AKT activation, cell proliferation, and oncogenic functions including focus formation and apoptosis resistance. Cell-based phosphorylation assays, non-phosphorylable K-Ras mutant (S181A), p120GAP activity assay, proliferation and focus formation assays Oncogene Medium 20802526
2016 Ca2+/calmodulin extracts K-Ras4B from negatively charged membranes in a nucleotide-independent manner, and the CaM/K-Ras4B complex does not bind membranes, demonstrating that CaM regulates K-Ras4B plasma membrane localization by sequestering it from the bilayer. This mechanism differs from PDEδ-mediated regulation. Fluorescence/FRET spectroscopy, FCS, and imaging in heterogeneous model biomembranes with GDP- and GTP-loaded K-Ras4B Biophysical journal Medium 27410739
2005 K-Ras4B associates dynamically with the plasma membrane and undergoes rapidly reversible binding; using rapamycin-regulated heterodimerization, K-Ras4B or its targeting sequence alone can transfer from the plasma membrane to mitochondria within minutes, unlike multiply lipid-modified constructs anchored to the PM. Fluorescence microscopy, rapamycin-regulated protein heterodimerization, live cell imaging Molecular biology of the cell Medium 16236799
2019 BI-2852 binds with nanomolar affinity to the switch I/II pocket between switch I and II of KRAS (present in both active and inactive forms), blocking all GEF, GAP, and effector interactions with KRAS simultaneously, leading to inhibition of downstream signaling and antiproliferative effects in KRAS mutant cells. Structure-based drug design, biochemical binding assay, GEF/GAP/effector interaction assays, cell proliferation assay Proceedings of the National Academy of Sciences of the United States of America High 31332011
2012 KRAS is poorly translated relative to HRAS due to enrichment in rare codons. Converting rare to common codons increases KRas protein expression and tumorigenicity to mirror that of HRas, demonstrating that synonymous codon usage is a hardwired regulatory mechanism controlling KRas protein levels and oncogenic activity. Codon-optimized KRAS expression constructs, protein expression quantification, tumorigenicity assays Current biology : CB Medium 23246410
2018 K-RAS4B localized to the plasma membrane via prenylation adopts an orientation in which the membrane occludes the effector-binding site when a small molecule (Cmpd2) simultaneously engages a shallow pocket on KRAS and associates with the lipid bilayer, thereby reducing RAF binding and impairing RAF activation. NMR spectroscopy of prenylated K-RAS4B in lipid bilayer, RAF binding assay, cell signaling assay Cell chemical biology Medium 30122370
2017 Phosphorylation at Ser181 reduces K-Ras4B membrane binding affinity without fully preventing membrane binding or clustering, and phosphorylated K-Ras4B maintains tight association with its cytosolic shuttle protein PDEδ; cells receiving a non-hydrolyzable phosphoserine mimetic show decreased plasma membrane distribution compared to non-phosphorylable K-Ras4B. Chemically synthesized K-Ras4B bearing phosphate, farnesyl and methyl modifications, model biomembrane binding assays, cell microinjection ACS chemical biology High 28448716
2010 Recombinant K-Ras4B interacts with lipids and this interaction is mediated by its C-terminal hypervariable region, as demonstrated using phospholipid bilayer nanodiscs. Nanodisc reconstitution, NMR, protein purification Protein expression and purification Medium 20566322
2001 Wild-type Kras2 functions as a tumor suppressor in lung tumorigenesis: heterozygous Kras2-deficient mice show increased susceptibility to chemically-induced lung tumors, wild-type Kras2 inhibits colony formation and tumor development by cells with activated Kras2, and an inverse correlation exists between wild-type Kras2 expression and ERK activity. Mouse tumor bioassay with Kras2-deficient mice, colony formation assay, tumor xenograft, ERK activity measurement Nature genetics High 11528387
2016 Kras is the unique Ras family member required for B cell development: hematopoietic-specific deletion of Kras impairs early B cell development at the pre-B cell stage and late maturation, and Kras deficiency specifically impairs pre-BCR- and BCR-induced activation of the Raf-1/MEK/ERK pathway in pre-B and mature B cells. Conditional Kras knockout mice, bone marrow chimeras with B cell-specific Kras deletion, B cell development analysis, Raf-1/MEK/ERK pathway analysis Journal of immunology High 26773157
2024 KRAS-dependent transcription in KRAS-mutant cancers is driven predominantly through the ERK MAPK cascade. ERK deregulates the anaphase-promoting complex/cyclosome (APC/C) and other cell cycle machinery components as key processes driving PDAC growth, revealed by integration of KRAS/ERK-dependent transcriptome with ERK-regulated phospho- and total proteome. Genome-scale loss-of-function, RNA-seq, phosphoproteomics, total proteomics in KRAS-mutant cancer lines and patient data Science High 38843331
2023 Allosteric communication in KRAS propagates particularly effectively across the central β-sheet, and multiple surface pockets are genetically validated as allosterically active, including a distal pocket in the C-terminal lobe. Allosteric mutations typically inhibit binding to all tested effectors but can also change binding specificity, revealing potential to tune pathway activation. Deep mutational scanning of >26,000 KRAS mutations measuring effects on folding and binding to six interaction partners; genetic interaction analysis in double mutants to infer >22,000 causal free energy changes Nature High 38109937
2022 Feedback reactivation of RAS-MAPK signaling upon KRASG12C inhibition is driven by upstream feedback activation of wild-type RAS (not by a shift of KRASG12C to GTP-bound state), and multiple receptor tyrosine kinases can drive this reactivation in a KRASG12C-independent manner. Biochemical assays distinguishing KRASG12C-GTP vs wild-type RAS-GTP, RTK perturbation experiments, cell signaling analysis in NSCLC and CRC models Cell reports Medium 35732135
2015 The disordered HVR of K-Ras4B undergoes auto-inhibition by shielding the effector binding site in the GDP-bound state, with release upon GTP binding or certain oncogenic mutations; oncogenic mutations G12V/G12D modulate HVR-phospholipid binding specificity toward preferential interactions with phosphatidic acid. NMR spectroscopy, phospholipid binding specificity experiments with oncogenic K-Ras4B mutants Current opinion in structural biology Low 26709496
2025 ASP3082, a KRASG12D-selective degrader, induces KRASG12D protein degradation via a lysosome-dependent (VHL-mediated) process with remarkable selectivity, as shown by a crystal structure of the drug-induced ternary complex KRASG12D/ASP3082/VHL, with tumor regression in KRASG12D xenografts. Crystal structure of ternary complex, in vitro degradation assay, xenograft tumor model Communications chemistry High 40849515
2024 SRC kinase drives multidrug resistance to KRASG12C inhibition by activating the transcription factor JUN, which drives ABCC1 (multidrug transporter) expression. A genome-wide CRISPR screen identified ABCC1 as a resistance mediator, and SRC inhibitors (dasatinib, bosutinib) synergize with the KRASG12C inhibitor MRTX849 by blocking SRC-dependent JUN activation. Genome-wide CRISPR screen, JUN/ABCC1 pathway analysis, SRC inhibitor combination assays in cell lines, organoids, and mouse models Science advances High 39661665
2012 K-Ras4B forms dimers in vitro, observable with fully processed (farnesylated, methylated) protein preparations, suggesting dimerization could be important for activity and membrane interactions. In vitro biochemical characterization of purified K-Ras4B lipoprotein Protein expression and purification Low 22569482
2023 CAF-derived NRG1 activates cancer cell ERBB2 and ERBB3 receptor tyrosine kinases to support KRAS*-independent growth in PDAC. Genetic extinction or pharmacological inhibition of KRAS* upregulates ERBB2 and ERBB3 in cancer cells, prompting use of CAF-derived NRG1 as a survival factor; inhibition of ERBB2/3 or NRG1 abolished KRAS* bypass. Genetic depletion and pharmacological inhibition of KRAS*, ERBB2/3, and NRG1 in mouse and human PDAC models, co-culture experiments Genes & development Medium 37775182

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 KRAS mutation: from undruggable to druggable in cancer. Signal transduction and targeted therapy 831 34776511
2014 KRAS: feeding pancreatic cancer proliferation. Trends in biochemical sciences 566 24388967
2019 Drugging an undruggable pocket on KRAS. Proceedings of the National Academy of Sciences of the United States of America 336 31332011
2018 Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature 336 29364867
2004 An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis. Nature genetics 336 15608639
2017 KRAS Alleles: The Devil Is in the Detail. Trends in cancer 294 28958387
2010 Clinical relevance of KRAS in human cancers. Journal of biomedicine & biotechnology 294 20617134
2021 KRAS mutation in pancreatic cancer. Seminars in oncology 286 33676749
2019 Targeting the untargetable KRAS in cancer therapy. Acta pharmaceutica Sinica. B 273 31649840
2022 Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants. Cancer discovery 260 35046095
2015 KRAS as a Therapeutic Target. Clinical cancer research : an official journal of the American Association for Cancer Research 258 25878360
2001 Wildtype Kras2 can inhibit lung carcinogenesis in mice. Nature genetics 258 11528387
2024 Targeting KRAS in cancer. Nature medicine 236 38637634
2020 KRAS: From undruggable to a druggable Cancer Target. Cancer treatment reviews 215 32711246
2018 KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS. Cell 213 29336889
2013 KRAS mutation: should we test for it, and does it matter? Journal of clinical oncology : official journal of the American Society of Clinical Oncology 202 23401440
2012 KRAS mutations in lung cancer. Clinical lung cancer 187 23122493
2016 The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B. Scientific reports 183 26902995
2015 GTP-Dependent K-Ras Dimerization. Structure (London, England : 1993) 176 26051715
2012 KRAS mutation testing in metastatic colorectal cancer. World journal of gastroenterology 171 23066310
1995 Disruption of oncogenic K-Ras4B processing and signaling by a potent geranylgeranyltransferase I inhibitor. The Journal of biological chemistry 168 7592913
2021 The KRAS-G12C inhibitor: activity and resistance. Cancer gene therapy 162 34471232
2016 KRAS-related proteins in pancreatic cancer. Pharmacology & therapeutics 155 27595930
2022 KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy. Cell reports 137 35732135
2018 Differential Effector Engagement by Oncogenic KRAS. Cell reports 122 29444439
2012 Rare codons regulate KRas oncogenesis. Current biology : CB 118 23246410
2000 The basis for K-Ras4B binding specificity to protein farnesyltransferase revealed by 2 A resolution ternary complex structures. Structure (London, England : 1993) 112 10673434
2019 KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis. Proceedings of the National Academy of Sciences of the United States of America 106 31611389
2023 The energetic and allosteric landscape for KRAS inhibition. Nature 104 38109937
2010 EGFR and KRAS in colorectal cancer. Advances in clinical chemistry 101 20857619
2024 Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers. Science (New York, N.Y.) 94 38843331
2022 Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming. Cellular and molecular gastroenterology and hepatology 80 35245687
2018 Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site. Cell chemical biology 78 30122370
2005 K-ras4B and prenylated proteins lacking "second signals" associate dynamically with cellular membranes. Molecular biology of the cell 75 16236799
2021 Oncogenic KRAS: Signaling and Drug Resistance. Cancers 73 34830757
2017 Calmodulin and PI3K Signaling in KRAS Cancers. Trends in cancer 69 28462395
2021 Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges. Molecular cancer 66 34607583
2024 Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer. Current issues in molecular biology 63 38666907
2018 K-Ras4B Remains Monomeric on Membranes over a Wide Range of Surface Densities and Lipid Compositions. Biophysical journal 63 29320680
2019 The Role of KRAS in Endometrial Cancer: A Mini-Review. Anticancer research 59 30711927
2010 K-Ras4B phosphorylation at Ser181 is inhibited by calmodulin and modulates K-Ras activity and function. Oncogene 59 20802526
2024 Targeting KRAS in pancreatic cancer. Oncology research 58 38686056
2019 Small Molecule KRAS Agonist for Mutant KRAS Cancer Therapy. Molecular cancer 58 30971271
2021 Targeting KRAS: The Elephant in the Room of Epithelial Cancers. Frontiers in oncology 57 33777798
2009 The hypervariable region of K-Ras4B is responsible for its specific interactions with calmodulin. Biochemistry 57 19583261
2021 KRAS/LKB1 and KRAS/TP53 co-mutations create divergent immune signatures in lung adenocarcinomas. Therapeutic advances in medical oncology 52 33995590
2025 Targeting KRAS: from metabolic regulation to cancer treatment. Molecular cancer 50 39799325
2018 KRAS induces lung tumorigenesis through microRNAs modulation. Cell death & disease 50 29440633
2022 Glimmers of hope for targeting oncogenic KRAS-G12D. Cancer gene therapy 49 36414681
2021 Stopping the beating heart of cancer: KRAS reviewed. Current opinion in structural biology 49 34303932
2017 Intrinsic protein disorder in oncogenic KRAS signaling. Cellular and molecular life sciences : CMLS 49 28597297
2017 Deciphering lipid codes: K-Ras as a paradigm. Traffic (Copenhagen, Denmark) 48 29120102
2022 Targeting the undruggable oncogenic KRAS: the dawn of hope. JCI insight 47 35014625
2009 KRAS mutation, KRAS-LCS6 polymorphism, and non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 47 19854534
2018 KRAS: Reasons for optimism in lung cancer. European journal of cancer (Oxford, England : 1990) 45 29894909
2016 Regulation of K-Ras4B Membrane Binding by Calmodulin. Biophysical journal 43 27410739
2003 LOH of chromosome 12p correlates with Kras2 mutation in non-small cell lung cancer. Oncogene 42 12606951
2022 Overcoming KRAS-Mutant Lung Cancer. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 41 35412860
2015 The disordered hypervariable region and the folded catalytic domain of oncogenic K-Ras4B partner in phospholipid binding. Current opinion in structural biology 41 26709496
2022 More to the RAS Story: KRASG12C Inhibition, Resistance Mechanisms, and Moving Beyond KRASG12C. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 40 35561303
2024 The next-generation KRAS inhibitors…What comes after sotorasib and adagrasib? Lung cancer (Amsterdam, Netherlands) 39 39047616
2022 KRAS: A Druggable Target in Colon Cancer Patients. International journal of molecular sciences 39 35456940
2021 Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors. Pharmaceutics 38 34064352
2023 The Therapeutic Landscape for KRAS-Mutated Colorectal Cancers. Cancers 37 37190303
2024 KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance. Current oncology (Toronto, Ont.) 36 38668053
1996 Coamplification in tumors of KRAS2, type 2 inositol 1,4,5 triphosphate receptor gene, and a novel human gene, KRAG. Genomics 35 8661122
2025 "Undruggable KRAS": druggable after all. Genes & development 33 39638567
2017 Phosphorylation Weakens but Does Not Inhibit Membrane Binding and Clustering of K-Ras4B. ACS chemical biology 33 28448716
2020 Targeting Mutant KRAS in Pancreatic Cancer: Futile or Promising? Biomedicines 30 32796566
2021 Targeting mutated GTPase KRAS in tumor therapies. European journal of medicinal chemistry 29 34520956
2016 K-Ras4B/calmodulin/PI3Kα: A promising new adenocarcinoma-specific drug target? Expert opinion on therapeutic targets 28 26873344
2024 Structural insights into small-molecule KRAS inhibitors for targeting KRAS mutant cancers. European journal of medicinal chemistry 27 39167893
2021 Targeting KRAS in Colorectal Cancer. Current oncology reports 27 33582927
2024 A pan-KRAS degrader for the treatment of KRAS-mutant cancers. Cell discovery 25 38937452
2014 KRAS mutations: analytical considerations. Clinica chimica acta; international journal of clinical chemistry 25 24534449
2022 Interplay between K-RAS and miRNAs. Trends in cancer 24 35093302
2016 Kras Is Critical for B Cell Lymphopoiesis. Journal of immunology (Baltimore, Md. : 1950) 24 26773157
2023 KRAS mutations and endometriosis burden of disease. The journal of pathology. Clinical research 23 36977195
2025 Discovery of KRAS(G12D) selective degrader ASP3082. Communications chemistry 22 40849515
2023 KRAS Hijacks the miRNA Regulatory Pathway in Cancer. Cancer research 22 36946612
2023 CBX4 deletion promotes tumorigenesis under KrasG12D background by inducing genomic instability. Signal transduction and targeted therapy 22 37696812
2023 Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer. Genes & development 22 37775182
2021 AMPKα loss promotes KRAS-mediated lung tumorigenesis. Cell death and differentiation 22 34040167
2018 Oncogenic KRas mobility in the membrane and signaling response. Seminars in cancer biology 22 29499269
2022 Realgar‑induced KRAS mutation lung cancer cell death via KRAS/Raf/MAPK mediates ferroptosis. International journal of oncology 21 36321791
2021 Targeting mutant KRAS. Current opinion in chemical biology 21 33838397
2019 Detection of KRAS mutation via ligation-initiated LAMP reaction. Scientific reports 21 30976068
2019 Activating Mutations in PTPN11 and KRAS in Canine Histiocytic Sarcomas. Genes 21 31277422
2010 Imaging human pancreatic cancer xenografts by targeting mutant KRAS2 mRNA with [(111)In]DOTA(n)-poly(diamidopropanoyl)(m)-KRAS2 PNA-D(Cys-Ser-Lys-Cys) nanoparticles. Bioconjugate chemistry 21 20232877
2023 Immune vulnerabilities of mutant KRAS in pancreatic cancer. Trends in cancer 20 37524642
2021 KRAS G12C fragment screening renders new binding pockets. Small GTPases 20 34558391
2021 KRAS signaling in malignant pleural mesothelioma. EMBO molecular medicine 20 34898002
2019 miR-548d-3p inhibits osteosarcoma by downregulating KRAS. Aging 20 31327761
2024 SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition. Science advances 19 39661665
2014 KRAS and BRAF mutations in anal carcinoma. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 19 25244542
2019 Oncogenic BRAF and KRAS mutations in endosalpingiosis. The Journal of pathology 18 31576556
2012 K-Ras4B lipoprotein synthesis: biochemical characterization, functional properties, and dimer formation. Protein expression and purification 18 22569482
2010 Expression, purification, and characterization of soluble K-Ras4B for structural analysis. Protein expression and purification 18 20566322
2023 Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies. Advances in cancer research 17 37268395
2021 Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers. Cancers 17 34680229

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