Affinage

KRAS

GTPase KRas · UniProt P01116

Round 2 corrected
Length
189 aa
Mass
21.7 kDa
Annotated
2026-04-28
130 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KRAS encodes a small GTPase that cycles between GDP-bound (inactive) and GTP-bound (active) states, transducing signals from receptor tyrosine kinases through effector pathways including RAF-MEK-ERK, PI3K-AKT, and RalGDS to control cell proliferation, survival, and metabolism (PMID:8493579, PMID:29444439). Oncogenic mutations at codons 12, 13, and 61 impair GAP-mediated GTP hydrolysis, locking KRAS in the active state and constitutively driving downstream signaling; these mutations are near-universal early events in pancreatic and colorectal carcinogenesis (PMID:2453289, PMID:2648401, PMID:26902995). Membrane association via C-terminal farnesylation and the polybasic hypervariable region is essential for signaling, and this region also mediates nucleotide-state-dependent autoinhibition of the effector-binding site, calmodulin-dependent membrane extraction feeding PI3Kα activation, and regulation by phosphorylation at Ser-181 (PMID:26682817, PMID:19583261, PMID:27410739, PMID:28448716). Oncogenic KRAS reprograms glutamine metabolism through a non-canonical GOT1-dependent pathway to maintain redox balance, signals predominantly through ERK to deregulate APC/C and cell-cycle machinery, and its protein output is constrained by rare codon usage that acts as a built-in tumor-suppressive mechanism (PMID:23535601, PMID:38843331, PMID:23246410, PMID:25437878).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1988 High

    Establishing that KRAS mutations are a near-universal initiating event in pancreatic cancer answered whether a single oncogene could account for virtually all cases of this malignancy and defined KRAS as the central driver.

    Evidence PCR-based mutation detection in 22 primary pancreatic carcinomas and colon tumors with staged tissue analysis

    PMID:2453289 PMID:2648401

    Open questions at the time
    • Mechanism by which mutant KRAS drives tumorigenesis was undefined
    • No effector pathway specificity was determined
    • Functional contribution versus passenger role not formally tested
  2. 1993 High

    Identification of SOS1 as the GEF coupling RTKs to RAS via GRB2 resolved how extracellular signals activate KRAS, placing it downstream of growth factor receptors.

    Evidence In vitro GEF reconstitution, yeast complementation, co-immunoprecipitation

    PMID:8493579

    Open questions at the time
    • How GAP-mediated inactivation was specifically impaired by oncogenic mutations remained structural speculation
    • Isoform-specific GEF regulation was not addressed
  3. 1995 High

    Discovery that K-Ras4B can be alternatively geranylgeranylated explained the clinical failure of farnesyltransferase inhibitors against KRAS-driven cancers, revealing redundancy in prenylation.

    Evidence In vitro prenylation assays and cell-based processing/MAPK assays with FTI and GGTase I inhibitors

    PMID:12882980 PMID:7592913

    Open questions at the time
    • Structural basis for K-Ras4B's dual prenylation susceptibility was not resolved
    • In vivo pharmacological confirmation was lacking
  4. 2000 High

    Crystal structures of K-Ras4B peptide–FTase complexes revealed how the polybasic HVR confers the highest FTase affinity among Ras isoforms, providing structural understanding of C-terminal processing.

    Evidence X-ray crystallography at 2 Å resolution of ternary FTase complexes

    PMID:10673434

    Open questions at the time
    • Full-length K-Ras4B structure with lipid modifications was unavailable
    • Mechanism of alternative geranylgeranylation was not structurally addressed
  5. 2009 High

    NMR and calorimetry defined the calmodulin–K-Ras4B HVR interaction and a genome-wide RNAi screen identified TBK1 as a synthetic lethal partner, jointly revealing non-canonical signaling outputs and vulnerabilities of mutant KRAS.

    Evidence NMR/ITC for CaM binding; genome-wide RNAi screen with mechanistic epistasis in KRAS-mutant cell lines

    PMID:19583261 PMID:19847166

    Open questions at the time
    • Whether CaM-dependent extraction operates in vivo was not shown
    • TBK1 synthetic lethality was not validated in clinical settings
  6. 2012 High

    Demonstrating that KRAS rare codon bias limits protein expression and that codon optimization increases tumorigenicity uncovered a hard-wired translational tumor suppressor mechanism embedded in the coding sequence.

    Evidence Isogenic codon-optimized transgenes with transformation assays in vitro; knock-in mice with codon-optimized Kras exon 3 and carcinogenesis assays

    PMID:23246410 PMID:25437878

    Open questions at the time
    • The ribosomal or tRNA mechanisms mediating rare-codon suppression were not identified
    • Whether codon bias affects mutant vs. wild-type KRAS differentially was not resolved
  7. 2013 High

    Isotope tracing revealed that oncogenic KRAS reprograms glutamine metabolism through a non-canonical GOT1-dependent pathway to maintain NADPH and redox balance, establishing metabolic rewiring as a core function of mutant KRAS in PDAC.

    Evidence 13C-glutamine flux analysis, siRNA knockdown of pathway enzymes, xenograft validation

    PMID:23535601

    Open questions at the time
    • Whether this pathway operates in KRAS-mutant cancers beyond PDAC was untested
    • Direct transcriptional mechanism linking KRAS to enzyme expression was incompletely defined
  8. 2015 High

    Biophysical studies established that the K-Ras4B HVR autoinhibits the effector-binding site in the GDP state with ~100-fold selectivity, and that GTP-bound K-Ras4B forms homodimers at two distinct interfaces, resolving how intramolecular and intermolecular interactions regulate effector access.

    Evidence NMR/SPR/ITC for autoinhibition; analytical ultracentrifugation, SAXS, and MD for dimerization

    PMID:26051715 PMID:26682817

    Open questions at the time
    • Dimerization interfaces lacked cell-based validation
    • Whether autoinhibition is modulated by specific lipid environments was unknown
  9. 2016 High

    Conditional knockout of Kras in hematopoietic cells demonstrated a non-redundant requirement for KRAS in B cell lymphopoiesis through the Raf-1/MEK/ERK axis, establishing a physiological developmental role distinct from oncogenesis.

    Evidence Hematopoietic- and B cell-specific conditional KO mice, bone marrow chimeras, signaling assays

    PMID:26773157

    Open questions at the time
    • Whether KRAS has analogous non-redundant roles in other non-hematopoietic lineages was not tested
    • Mechanism for KRAS isoform specificity in B cells was unclear
  10. 2016 High

    Studies of Ser-181 phosphorylation, PDEδ shuttling, and calmodulin-mediated membrane extraction defined three orthogonal mechanisms controlling K-Ras4B plasma membrane residence, clarifying how localization is dynamically regulated.

    Evidence Semisynthetic phosphorylated/farnesylated K-Ras4B on supported bilayers; SPR/FCS/FRET with CaM and PDEδ

    PMID:27410739 PMID:28448716

    Open questions at the time
    • Relative contributions of CaM, PDEδ, and phosphorylation in living cells were not quantified
    • Whether these mechanisms are differentially engaged in mutant vs. WT KRAS was not resolved
  11. 2018 High

    Genetic evidence that KRAS dimerization at the α4-α5 interface mediates fitness of KRAS-mutant cells and MEK inhibitor resistance provided a structural rationale for wild-type KRAS dependency in mutant KRAS tumors, though single-molecule studies challenged whether full-length processed K-Ras4B dimerizes on membranes.

    Evidence KRASD154Q dimerization-deficient mutant in LOH model and tumor assays; single-molecule FCS on supported lipid bilayers

    PMID:29320680 PMID:29336889

    Open questions at the time
    • Discrepancy between cell-based genetic dimerization data and biophysical monomeric behavior on bilayers is unresolved
    • Whether scaffold proteins mediate dimerization in cells was not tested
  12. 2019 High

    Structure-based drug design yielded compounds targeting two distinct KRAS pockets—BI-2852 at the switch I/II interface blocking all GEF/GAP/effector interactions, and Cmpd2 stabilizing membrane-occluded KRAS—proving KRAS is druggable at multiple sites.

    Evidence X-ray crystallography and NMR with biochemical competition and cell-based signaling assays

    PMID:30122370 PMID:31332011

    Open questions at the time
    • In vivo efficacy and selectivity of these compounds were not demonstrated
    • Whether these sites are accessible in all KRAS mutant contexts was untested
  13. 2021 High

    Clinical genomics and deep mutational scanning systematically mapped the resistance landscape to KRASG12C inhibitors, revealing that secondary KRAS mutations, gene amplification, and RTK-driven wild-type RAS reactivation represent convergent escape mechanisms.

    Evidence Paired pre-/post-treatment biopsy sequencing; in vitro deep mutational scanning; RAS activity assays with RTK inhibitor combinations

    PMID:34161704 PMID:35732135

    Open questions at the time
    • Therapeutic strategies to preempt multi-mechanism resistance were not clinically validated
    • Whether resistance mechanisms differ across tissue types was not systematically tested
  14. 2021 High

    Multi-omic profiling showed that KRAS-dependent transcription in PDAC is driven predominantly through ERK/MAPK, with APC/C and cell-cycle machinery as key downstream effectors, revising the canonical KRAS transcriptional signature.

    Evidence Inducible KRAS knockdown with integrated transcriptomics, phosphoproteomics, proteomics, and patient tumor data

    PMID:38843331

    Open questions at the time
    • Whether APC/C deregulation is a direct or indirect effect of ERK signaling was not distinguished
    • Contribution of non-ERK effectors to KRAS-dependent transcription was not fully quantified
  15. 2023 High

    A comprehensive deep mutational scan of >26,000 KRAS mutations mapped the allosteric network across the central β-sheet and identified multiple allosterically active surface pockets, providing a near-complete biophysical atlas of KRAS function.

    Evidence Deep mutational scanning with double-mutant epistasis and free energy inference across six binding partners

    PMID:38109937

    Open questions at the time
    • Structural validation of newly identified allosteric pockets by crystallography or cryo-EM is pending
    • Whether allosteric mutations differentially affect KRAS signaling in cellular contexts was not tested
  16. 2023 High

    CAF-derived NRG1 activating ERBB2/3 was identified as a microenvironment-driven bypass mechanism enabling KRAS-independent PDAC survival, demonstrating that KRAS-targeted therapy must account for paracrine escape.

    Evidence Genetic KRAS extinction, co-culture paracrine models, pharmacological ERBB inhibition in mouse and human PDAC

    PMID:37775182

    Open questions at the time
    • Whether NRG1-ERBB bypass operates in non-pancreatic KRAS-mutant cancers is unknown
    • The full repertoire of microenvironment-mediated escape routes has not been mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether KRAS dimerization occurs on native plasma membranes under physiological conditions, the complete structural basis for isoform-specific effector engagement in vivo, and how to therapeutically target the full spectrum of resistance mechanisms arising during KRAS inhibitor treatment.
  • No consensus on in vivo KRAS dimerization stoichiometry or scaffold dependency
  • Full-length, lipid-modified KRAS structure in a membrane environment is unavailable
  • Clinical strategies to preempt convergent resistance remain undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 4 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 6 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 4 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 1
Partners
BRAFCALM1PDEDPIK3CARAF1SOS1USP18YAP1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 Oncogenic mutations at codon 12 of c-K-ras (KRAS) are present in 21 of 22 human pancreatic carcinomas, establishing KRAS mutation as a near-universal and early critical event in exocrine pancreatic oncogenesis. PCR amplification and RNase A mismatch cleavage mutation detection on primary tumor and metastasis specimens Cell High 2453289
1989 KRAS2 codon 12 mutations occur early in human colon carcinoma development, preceding ploidy changes and existing in diploid cells from which aneuploid subpopulations arise; mutations can be present in histologically normal mucosa adjacent to carcinoma. Histological enrichment, cell sorting, PCR amplification, and direct DNA sequencing of colon carcinomas, adenomas, and adjacent normal tissue Proceedings of the National Academy of Sciences of the United States of America High 2648401
1993 Human SOS1 (hSos1) functions as a guanine nucleotide exchange factor (GEF) for RAS, with its CDC25-related domain specifically stimulating guanine nucleotide exchange on mammalian Ras proteins in vitro; hSos1 binds GRB2 via SH3 domain interactions, coupling receptor tyrosine kinases to RAS/KRAS signaling. In vitro GEF assay, yeast complementation, co-immunoprecipitation, overexpression in mammalian cells Science High 8493579
1995 K-Ras4B processing is more sensitive to inhibition by geranylgeranyltransferase I (GGTase I) inhibitor GGTI-286 than to farnesyltransferase inhibitor FTI-277, demonstrating that K-Ras4B can be alternatively geranylgeranylated and that its oncogenic signaling can be disrupted by GGTase I inhibition. In vitro prenylation assays, whole-cell processing assays, MAP kinase activity assays in intact cells The Journal of biological chemistry High 7592913
2000 Crystal structures of rat farnesyltransferase (FTase) ternary complexes with farnesyl diphosphate analogs and K-Ras4B peptide substrates revealed that the K-Ras4B polybasic region forms a type I beta turn and binds along the rim of the hydrophobic cavity, conferring the highest affinity of any natural FTase substrate; zinc is essential for productive Ca1a2X peptide binding. X-ray crystallography of ternary complexes at 2 Å resolution Structure High 10673434
2003 K-Ras4B resistance to farnesyltransferase inhibitors (FTIs) arises from two independent mechanisms: (1) its polybasic domain increases affinity for FTase, and (2) its CAAX motif can be alternatively geranylgeranylated. Either the polybasic domain alone or an alternatively prenylated CAAX alone renders K-Ras4B FTI-resistant, and K-Ras4B function is independent of the identity of the prenyl group. Chimeric Ras protein constructs, Elk-1 activation assays, anchorage-independent colony formation, microarray analysis The Journal of biological chemistry High 12882980
2009 The C-terminal hypervariable region (HVR) of K-Ras4B, specifically its polybasic farnesylated tail, is responsible for isoform-specific interaction with calmodulin (CaM); the HVR binds the C-terminal domain of Ca2+-loaded CaM with micromolar affinity, while the GTP-loaded catalytic domain may additionally interact with the N-terminal CaM domain, linking nucleotide state to CaM binding. NMR spectroscopy, isothermal titration calorimetry (ITC) Biochemistry High 19583261
2009 TBK1 is a synthetic lethal partner of oncogenic KRAS; TBK1 selectively activates NF-κB anti-apoptotic signals (via c-Rel and BCL-XL) in KRAS-mutant cancer cells, and its suppression induces apoptosis specifically in KRAS-dependent cells. Genome-wide RNA interference screen, mechanistic validation by epistasis and apoptosis assays in human cancer cell lines Nature High 19847166
2012 KRAS is enriched for rare codons relative to HRAS, limiting KRAS protein expression. Converting rare to common codons increases K-Ras expression and tumorigenicity to mirror that of H-Ras, demonstrating that synonymous nucleotide differences affecting codon usage underlie differences in HRas vs KRas expression and oncogenic function. Synonymous codon-optimized transgenes expressed from identical loci, protein expression quantification, transformation assays Current biology High 23246410
2013 Oncogenic KRAS reprograms glutamine metabolism in pancreatic ductal adenocarcinoma (PDAC) via transcriptional upregulation of RREBP1 and MYC and downregulation of GLUD1: PDAC cells use a non-canonical pathway converting glutamine-derived aspartate to oxaloacetate (via GOT1), then to malate and pyruvate, maintaining NADPH/NADP+ ratio and redox balance. Knockdown of any enzyme in this pathway suppresses PDAC growth in vitro and in vivo. Isotope tracing with 13C-glutamine, siRNA knockdown, xenograft tumor models, gene expression analysis Nature High 23535601
2014 YAP1 can substitute for oncogenic KRAS to rescue cell viability in KRAS-dependent cancer cells; KRAS and YAP1 converge on transcription factor FOS to activate a transcriptional program regulating the epithelial-mesenchymal transition (EMT). YAP1 is required for KRAS-induced cell transformation, and acquired resistance to Kras suppression in a murine lung cancer model involves increased YAP1 signaling. ORFeome rescue screen (15,294 ORFs) in KRAS-dependent cells with inducible KRAS shRNA, epistasis analysis, murine lung cancer model Cell High 24954536
2014 In mice, codon-optimized Kras alleles (Kras(ex3op)) producing more K-Ras protein from the endogenous locus lead to fewer carcinogen-induced tumors and induce growth arrest when oncogenically mutated, demonstrating that the rare codon bias of KRAS is a tumor-suppressive mechanism that limits oncogenic K-Ras protein levels in vivo. Knock-in mice with synonymous codon-optimized Kras exon 3, urethane carcinogenesis, tumor burden quantification The Journal of clinical investigation High 25437878
2015 The C-terminal HVR of K-Ras4B directly interacts with the active site/effector-binding region of the catalytic domain with ~100-fold higher affinity in the GDP-bound vs. GTP-bound state; HVR binding interferes with Ras-Raf interaction, modulates phospholipid binding, and slightly slows nucleotide exchange, establishing an autoinhibitory mechanism. NMR spectroscopy, surface plasmon resonance, isothermal titration calorimetry Biophysical journal High 26682817
2015 GTP-bound K-Ras4B forms stable homodimers; two major dimer interfaces were identified: a β-sheet interface overlapping effector binding sites (potentially inhibitory) and a helical interface that may promote Raf dimerization and activation. Ras self-association can regulate effector binding and activity. Analytical ultracentrifugation, molecular dynamics simulations, small-angle X-ray scattering Structure Medium 26051715
2015 K-Ras4B membrane binding is driven by farnesyl group insertion into disordered lipid microdomains; phosphorylation of Ser-181 prohibits spontaneous farnesyl membrane insertion; the polybasic polylysine sequence modulates specific binding to anionic phospholipids and farnesyl membrane orientation. Confocal microscopy, surface plasmon resonance, molecular dynamics simulations The Journal of biological chemistry Medium 25713064
2016 Molecular dynamics simulations reveal that oncogenic mutations G12C/G12D/G12V/G13D/Q61H differentially drive inactive-to-active conformational transitions in K-Ras4B-GTP; GAP not only donates its R789 arginine finger but stabilizes the catalytically competent conformation and pre-organizes Q61; oncogenic mutations disrupt R789/Q61 organization, impairing GAP-mediated GTP hydrolysis. 6.4 μs cumulative molecular dynamics simulations of WT and mutant K-Ras4B with and without GAP Scientific reports Medium 26902995
2016 Kras is required for B cell lymphopoiesis: hematopoietic-specific deletion of Kras impairs early B cell development at the pre-B cell stage and late B cell maturation. Kras deficiency specifically impairs pre-BCR- and BCR-induced activation of the Raf-1/MEK/ERK pathway, while T cell development is unaffected, demonstrating Kras as the unique Ras family member critical for the Raf-1/MEK/ERK axis in B cells. Conditional knockout mice (hematopoietic-specific and B cell-specific Cre), bone marrow chimeras, flow cytometry, proliferation and signaling assays Journal of Immunology High 26773157
2016 Phosphorylation at Ser-181 of K-Ras4B reduces but does not fully abolish membrane binding and clustering; phosphorylated K-Ras4B maintains association with cytosolic shuttle PDEδ; phosphorylation does not alter localization to liquid-disordered lipid subdomains but facilitates dissociation from the plasma membrane. Semisynthesis of triply modified K-Ras4B (phosphate + farnesyl + methyl), supported lipid bilayer studies, fluorescence spectroscopy, cell microinjection ACS Chemical Biology High 28448716
2016 Ca2+/calmodulin (CaM) extracts K-Ras4B from negatively charged membranes in a nucleotide-independent manner; the CaM/K-Ras4B complex is stable in the presence of anionic membranes and shows no membrane binding. PDEδ and CaM affect K-Ras4B membrane interaction through different mechanisms. Surface plasmon resonance, fluorescence spectroscopy (FCS, FRET), model membrane studies, FRAP Biophysical journal High 27410739
2017 Oncogenic KRAS drives a non-canonical glutamine-to-aspartate metabolic pathway through transcriptional regulation of key enzymes; the KRAS-regulated kinome in PDAC includes WEE1 among kinases downregulated upon KRAS loss, and combined WEE1 + ERK inhibition causes enhanced PDAC growth suppression and apoptosis. Multiplexed inhibitor bead/MS kinomics, siRNA knockdown, pharmacological inhibition, synergy studies in PDAC cell lines The Journal of biological chemistry Medium 34688654
2017 CaM preferentially binds unfolded K-Ras4B HVR (not α-helical HVR) using all three CaM domains; interaction is stabilized by docking of farnesyl to hydrophobic pockets in both CaM lobes; CaM wraps around the polybasic anchor region of HVR, enabling membrane extraction of K-Ras4B to form a K-Ras4B–CaM–PI3Kα ternary complex that activates PI3Kα. Molecular dynamics simulations, fluorescence binding experiments The Journal of biological chemistry Medium 28623230
2017 USP18 deubiquitinase stabilizes the KRAS oncoprotein; USP18 loss reduces KRAS protein half-life and mislocalizes KRAS from the plasma membrane; USP18 gain increases KRAS stability; Usp18 loss in Kras-mutant mice significantly reduces lung tumor burden. Cycloheximide chase, subcellular fractionation, conditional KO mice, immunohistochemistry Molecular Cancer Research Medium 28242811
2018 KRAS dimerization at the α4-α5 interface mediates wild-type KRAS-dependent fitness of KRAS-mutant lung adenocarcinoma cells and underlies resistance to MEK inhibition; KRASD154Q (dimerization-deficient mutant) abrogates these effects both in vitro and in vivo; dimerization also has a critical role in the oncogenic activity of mutant KRAS. Genetically inducible KRAS LOH model, dimerization-disrupting mutant KRASD154Q, MEK inhibitor response assays, in vitro and in vivo tumor models Cell High 29336889
2018 Full-length, fully processed (farnesylated + methylated) K-Ras4B lacks intrinsic dimerization capability on supported lipid bilayers across a wide range of surface densities and lipid compositions including cholesterol-containing membranes. Fluorescence correlation spectroscopy (FCS), single-molecule tracking on supported lipid bilayers with natively processed K-Ras4B Biophysical journal High 29320680
2018 K-Ras4B mutant (G12C/G12D) HVR shows preferential interaction with phosphatidic acid (PA) over other phospholipids; in the GDP-bound state the HVR shields the effector-binding site (autoinhibition); GTP binding and oncogenic mutations release HVR, enabling calmodulin interaction. Molecular dynamics simulations, NMR, phospholipid binding assays Current opinion in structural biology Medium 26709496
2018 A compound (Cmpd2) inhibits K-RAS4B by stabilizing membrane-dependent occlusion of the effector-binding site: it simultaneously engages a shallow pocket on KRAS and the lipid bilayer, orienting membrane-associated prenylated KRAS so the membrane sterically occludes the effector-binding site, reducing RAF binding and impairing RAF activation. NMR, lipid bilayer binding assays, cell-based RAF activation assays, structure-based mechanism elucidation Cell Chemical Biology High 30122370
2019 BI-2852 binds with nanomolar affinity to the switch I/II pocket on KRAS (present in both active and inactive forms), blocking all GEF, GAP, and effector interactions simultaneously, demonstrating that this pocket is druggable; binding inhibits downstream signaling and has antiproliferative effects in KRAS-mutant cells. Structure-based drug design, X-ray crystallography, biochemical GEF/GAP/effector competition assays, cell-based signaling assays Proceedings of the National Academy of Sciences of the United States of America High 31332011
2019 K-Ras4B allosterically activates PI3Kα by binding-induced conformational changes that disrupt p110/p85 (nSH2) interactions, exposing the kinase domain for membrane association and substrate phosphorylation; allosteric signaling is rewired from helical to kinase domain in the K-Ras4B/PI3Kα complex. Accelerated molecular dynamics simulations, allosteric pathway analysis, community network analysis International journal of biological macromolecules Low 31816384
2019 A small molecule KRAS agonist (KRA-533) binds the GTP/GDP-binding pocket of KRAS and prevents GTP cleavage, accumulating active GTP-KRAS; K117A mutation in KRAS abolishes KRA-533 binding and blocks its activity; KRA-533-mediated KRAS hyperactivation promotes apoptosis and autophagic cell death preferentially in KRAS-mutant cancer cells. GDP/GTP exchange assay, site-directed mutagenesis, cell viability assays, xenograft and GEMM models Molecular cancer Medium 30971271
2020 Urethane carcinogenesis specificity is determined by the sequence specificity of urethane mutagenesis coupled with transcription bias and isoform locus: the initiating Kras Q61L/R mutation was captured days after urethane exposure using error-corrected high-throughput sequencing, demonstrating that transcription rate and isoform-specific context drive RAS mutation tropism. Error-corrected high-throughput sequencing of mouse Ras genes at multiple time points post-carcinogen exposure Nature communications High 32286309
2021 KRAS-dependent transcription is driven predominantly through the ERK/MAPK cascade; KRAS-regulated ERK signaling deregulates the anaphase promoting complex/cyclosome (APC/C) and cell cycle machinery as key drivers of PDAC growth; the KRAS-dependent gene signature diverges substantially from the Hallmark KRAS signaling gene signature. Inducible KRAS knockdown, transcriptomics, phosphoproteomics, total proteomics, patient tumor data integration Science High 38843331
2022 Resistance to KRASG12C inhibitors is driven primarily by upstream feedback activation of wild-type RAS (rather than reactivation of KRASG12C to its GTP-bound state); multiple RTKs can independently drive this KRASG12C-independent RAS-MAPK reactivation; convergent upstream or downstream blockade can overcome resistance. RAS activity assays, RTK inhibitor combinations, cell signaling studies in KRASG12C-mutant cancer cells treated with G12C inhibitors Cell reports High 35732135
2023 Cancer-associated fibroblast (CAF)-derived NRG1 activates cancer cell ERBB2/ERBB3 receptor tyrosine kinases to support KRAS*-independent pancreatic cancer growth; genetic extinction of KRAS* upregulates ERBB2/ERBB3 in cancer cells, which then utilize paracrine CAF-NRG1 as a survival factor; ERBB2/3 or NRG1 depletion abolishes KRAS* bypass. Genetic KRAS extinction, pharmacological inhibition, paracrine co-culture models, mouse and human PDAC models Genes & development High 37775182
2023 A comprehensive deep mutational scan quantified >26,000 mutations' effects on KRAS folding and binding to six interaction partners, mapping >22,000 causal free energy changes; allosteric propagation is particularly effective across the central β-sheet; multiple surface pockets are validated as allosterically active including a distal C-terminal lobe pocket; most allosteric mutations inhibit all effectors but some can alter binding specificity. Deep mutational scanning, double-mutant genetic interaction analysis, free energy change inference Nature High 38109937
2021 Acquired resistance to adagrasib (KRASG12C inhibitor) involves diverse mechanisms including secondary KRAS mutations (G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C), KRAS amplification, and bypass alterations (MET amplification, NRAS/BRAF/MAP2K1/RET mutations, oncogenic fusions involving ALK/RET/BRAF/RAF1/FGFR3, NF1/PTEN loss); deep mutational scanning systematically defined the landscape of KRAS mutations conferring inhibitor resistance. Genomic sequencing of paired pre-/post-treatment biopsies, in vitro deep mutational scanning screen The New England journal of medicine High 34161704
2017 KRAS can bind numerous effector proteins (RAF, PI3K, RalGDS families, and others); combinatorial siRNA knockdown of 41 KRAS effector nodes in 92 cell lines identified two major subtypes of KRAS-mutant cancers with distinct effector dependencies, demonstrating that each cell line has a unique effector engagement pattern. Arrayed combinatorial siRNA screen of 41 effector nodes across 92 cancer cell lines, quantitative phenotype assessment Cell reports High 29444439

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. The New England journal of medicine 3068 19339720
2009 Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 2959 19847166
2008 K-ras mutations and benefit from cetuximab in advanced colorectal cancer. The New England journal of medicine 2921 18946061
2008 Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2528 18316791
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2005 Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. Journal of the National Cancer Institute 2027 15741570
1988 Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1932 2453289
2006 KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer research 1813 16618717
2013 Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. The New England journal of medicine 1802 24024839
2010 Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. The Lancet. Oncology 1728 20619739
2013 Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 1642 23535601
2012 A comprehensive survey of Ras mutations in cancer. Cancer research 1612 22589270
2009 Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1566 19667264
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2008 Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1310 19001320
2005 Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1231 16043828
2008 KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1208 18202412
2015 High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities. Cell 1200 26627737
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2009 Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. The New England journal of medicine 1065 19196673
2001 Nerve growth factor signaling, neuroprotection, and neural repair. Annual review of neuroscience 1029 11520933
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2009 Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 956 20008640
2021 Acquired Resistance to KRASG12C Inhibition in Cancer. The New England journal of medicine 949 34161704
2009 DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 888 19273710
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2016 Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 827 28039262
2014 Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. The Journal of biological chemistry 804 24398677
2021 KRAS mutation: from undruggable to druggable in cancer. Signal transduction and targeted therapy 796 34776511
1993 Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science (New York, N.Y.) 772 8493579
2014 KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 650 24954536
2018 Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature 334 29364867
2019 Drugging an undruggable pocket on KRAS. Proceedings of the National Academy of Sciences of the United States of America 328 31332011
2010 Clinical relevance of KRAS in human cancers. Journal of biomedicine & biotechnology 289 20617134
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