Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
Open accessAbstract
Cancer therapy by entrapment: Mutations in the KRAS oncogene occur at high frequency in several of the most lethal human cancers, including lung and pancreatic cancer. Substantial effort has thus been directed toward developing KRAS inhibitors. KRAS encodes an enzyme that binds the nucleotide GTP and hydrolyzes it to GDP. It had been thought that oncogenic mutations disable this hydrolytic activity, locking KRAS in the GTP-bound, active state. Surprisingly, Lito et al. found that a certain KRAS mutant (G12C) retains hydrolytic activity and continues to cycle between its active and inactive states. They describe a compound that inhibits KRAS(G12C) signaling and tumor cell growth by binding to the GDPbound form of KRAS, trapping it in its inactive state. Science , this issue p. 604
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Early preclinical studies with KRASG12C inhibitors such as ARS-1620 suggested adaptive feedback as a potential resistance mechanism.
“early preclinical studies with KRASG12C inhibitors, such as ARS-1620, have suggested a potential role for adaptive feedback as a mechanism of resistance (7) (15).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [7]
The paper’s indexed text (section labeled Abstract; page unavailable) reports that feedback-related RTK activation attenuated the inhibitory effect of ARS853 and suggests ways resistance to this class of drugs might emerge. It studies ARS853, not the cited example ARS-1620, so it does not directly support the claim for that compound. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIncreased RTK activity may lead to increased cycling of KRASG12C to its active GTP-bound form that hinders the binding of most KRASG12C inhibitors, which bind specifically to the inactive GDP-bound form.
“First, as described by Lito et al, increased RTK activity may lead to increased cycling of KRASG12C to its active GTP-bound form that hinders the binding of most KRASG12C inhibitors, which bind specifically to the inactive GDP-bound form (7).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [7]
In the supplied copy (section labeled Abstract; no page given), Lito et al. report that RTK-mediated nucleotide exchange affects inhibition and that increased exchange lowers the GDP-bound KRASG12C available for ARS853 binding. This supports the proposed mechanism for ARS853, but the paper does not establish that most KRASG12C inhibitors bind specifically to the GDP-bound form. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCompounds bind covalently to cysteine 12 in the switch II pocket of GDP-bound KRASG12C, preventing oncogenic signaling and causing tumor regressions in preclinical models.
“compounds have been identified that bind covalently to cysteine 12 within the switch II pocket of the GDP-bound form of the KRASG12C protein, preventing oncogenic signaling and causing potent tumor regressions in preclinical models.3-7”
From Acquired Resistance to KRAS <sup>G12C</sup> Inhibition in Cancer (2021) · cites this paper as [4]
The paper’s main text (indexed under Abstract; page unavailable) reports that ARS853 preferentially binds GDP-bound KRASG12C and suppresses KRAS-GTP and downstream signaling in mutant lung cancer cells. The passages do not establish covalent binding specifically to cysteine 12 in the switch II pocket, and they report cell-line growth inhibition and apoptosis—not potent tumor regressions in preclinical models. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe appreciable degree of nucleotide cycling observed in KRASG12C-mutant protein proved critical for the development of clinically active KRASG12C-selective inhibitors which bind the GDP-bound conformation and lock KRAS in the inactive state.
“Moreover, the appreciable degree of nucleotide cycling observed in KRAS G12C -mutant protein proved critical for the development of clinically active KRAS G12C -selective inhibitors which bind the GDP-bound conformation and lock KRAS in the inactive state [7-9].”
From Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor (2022) · cites this paper as [8]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredEGFR is a major mediator of adaptive feedback in colorectal cancer.
“Preclinical studies have identified EGFR as a major mediator of adaptive feedback, and concomitant blockade of EGFR has been shown to enhance the antitumor activity of KRAS G12C inhibition12,15.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [15]
The paper reports that EGFR inhibition enhanced the effects of the KRAS G12C inhibitor ARS853 in two lung cancer cell lines (Abstract, page not provided). It does not establish EGFR as a major mediator of adaptive feedback in colorectal cancer; it says the relevant receptor signaling in lung cancer varies from tumor to tumor. (LLM, conf=0.87)
Experimental — accuracy not yet measured
KRASG12C inhibitors lock mutant KRAS in an inactive GDP-bound state.
“The inhibitors function by locking KRASG12C in an inactive GDP bound state, exploiting the unique property of KRASG12C to cycle between the GDP- and GTP-bound states (6,7).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [7]
These resistance mutations probably increase the fraction of KRAS protein in the active GTP-bound form that does not bind the drug.
“These resistance mutations probably increase the fraction of KRAS protein in the active GTP-bound form that does not bind to the drug.4”
From Acquired Resistance to KRAS <sup>G12C</sup> Inhibition in Cancer (2021) · cites this paper as [4]
Concomitant blockade of EGFR enhances the antitumor activity of KRAS G12C inhibition.
“Preclinical studies have identified EGFR as a major mediator of adaptive feedback, and concomitant blockade of EGFR has been shown to enhance the antitumor activity of KRAS G12C inhibition12,15.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [15]
Concomitant RTK inhibition can increase the efficacy of KRAS G12C covalent inhibitors by maintaining KRAS G12C in a GDP-bound conformation, facilitating binding of the covalent inhibitor.
“Given this particular feature of the KRAS G12C mutant protein, the efficacy of these compounds can be increased by concomitant receptor tyrosine kinase (RTK) inhibition that further maintain KRAS G12C in a GDP-bound conformation, facilitating the binding of the covalent inhibitor(7-9).”
From EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. (2020) · cites this paper as [8]
RTK inhibition in NSCLC preclinical models can potentiate KRAS G12C covalent inhibitors by slowing down exchange factors favoring a GDP-bound status of KRAS.
“It is known that RTK inhibition in NSCLC preclinical models can potentiate KRAS G12C covalent inhibitors, by slowing down exchange factors favoring a GDP-bound status of KRAS(8).”
From EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. (2020) · cites this paper as [8]
ARS-853 suppresses K-RasG12C-dependent cell proliferation.
“ARS-853 was firstly selected as a potent inhibitor that suppresses K-RasG12C-dependent cell proliferation.4,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [49]
Binding of cysteine-reactive compounds to K-RasG12C induces structurally disordered switch I/II, which converts the GTP preference of naive K-RasG12C to GDP.
“The binding of these compounds to K-RasG12C induces structurally disordered switch I/II, which converts the GTP preference of naive K-RasG12C to GDP.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [49]
ARS-853 failed to demonstrate in vivo efficacy due to undesirable pharmacokinetics.
“However, it failed to demonstrate in vivo efficacy due to undesirable pharmacokinetics.4,5,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [49]
A large fraction of K-RasG12C protein is trapped in the inactive GDP-bound state, impairing its interaction with downstream effectors such as RAF.
“Consequently, a large fraction of K-RasG12C protein is trapped in the inactive GDP-bound state, which impairs its interaction with downstream effectors, such as rapidly accelerated fibrosarcoma kinase (RAF).3,4,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [49]
Secondary KRAS mutations confer intrinsic resistance to ARS-853 in KRASG12C mutant models by either potentiating nucleotide exchange (Y40A, N116H, or A146V) or impairing inherent GTPase activity (A59G, Q61L, or Y64A).
“For example, secondary KRAS mutations would confer intrinsic resistance to ARS-853 in KRASG12C mutant models by either potentiating nucleotide exchange (secondary mutation: Y40A, N116H, or A146V) or impairing inherent GTPase activity (secondary mutation: A59G, Q61L, or Y64A) (Figure 3D).49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [49]
K-RasG12C inhibitors act primarily through targeting the MAPK/ERK pathway for growth inhibition.
“Instead, K-RasG12C inhibitors act primarily through targeting MAPK/ERK pathway for growth inhibition.4, 5, 6, 7,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [49]
Preclinical findings strongly imply that intrinsic resistance might be accountable for heterogeneous responses to K-RasG12C inhibition in the clinic.
“These preclinical findings strongly imply that intrinsic resistance might be accountable for the heterogeneous responses to K-RasG12C inhibition in the clinic.4, 5, 6, 7,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [49]
In most KRASG12C mutant models, phosphorylation of AKT and mTORC1-effector ribosomal protein S6 is barely affected by K-RasG12C inhibition.
“In most KRASG12C mutant models, the phosphorylation status of AKT and mTORC1-effector ribosomal protein S6 is barely affected by K-RasG12C inhibition.6,7,12,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [49]
Co-treating KRASG12C mutant cancer cells with K-RasG12C inhibitors plus either MEK or ERK inhibitors produced inconsistent results, limiting the clinical use of these combinations.
“In line with the these findings, inconsistent results were observed co-treating KRASG12C mutant cancer cells with K-RasG12C inhibitors plus either MEK or ERK inhibitors, limiting the use of these drug combinations in the clinic.6,12,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [49]
The effect of ARS-853 was potentiated by EGFR inhibition in H2122 and Calu-1 cells.
“Lito et al.49 reported that the effect of ARS-853 was potentiated by EGFR inhibition in H2122 and Calu-1 cells.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [49]
Improved drug design has produced inhibitors selective for mutant KRAS in either its active or inactive state.
“improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [65]
KRASG12C inhibitors do not affect RAS signalling in non-malignant cells and theoretically carry a low risk of on-target, off-tumour toxicity.
“Accordingly, inhibitors of this type are KRASG12C specific; therefore, they do not affect RAS signalling in non-malignant cells65,70–72 and, at least theoretically, have a low risk of on-target, off-tumour toxicities.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [65]
KRASG12C is not permanently GTP-bound and depends on upstream RTK signaling for GEF-mediated GTP reloading.
“KRASG12C is not permanently GTP-bound and maintains a dependency on upstream receptor tyrosine kinase (RTK) signaling for GEF-mediated GTP reloading (9, 10).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [9]
The rationale for SHP2 and SOS1 inhibitors as pan-KRAS inhibitors is that several KRAS oncoproteins, including G12C, cycle between inactive and active states and rely on upstream activation and nucleotide exchange for full transforming potential.
“The rationale for pursuing SHP2 and SOS1 inhibitors as pan-KRAS inhibitors is grounded in the evidence that several (K)RAS oncoproteins, including KRASG12C, still cycle between an inactive and active state and rely on upstream activation and nucleotide exchange to exhibit their full transforming potential (9–13, 33, 34).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [9]
G12C inhibitors bind an evanescent pocket in KRAS-GDP, positioning a reactive group to couple to the mutant cysteine.
“G12C-Is bind an evanescent pocket in KRAS-GDP, positioning a reactive group to couple to the mutant cysteine.”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Lito et al., 2016
Initial KRASG12C-specific inhibitors showed only limited potency.
“follow-up studies indicated that these initial compounds showed only limited potency (39, 40).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [39]
Compound 12 binding to the switch II pocket impaired KRAS signalling by shifting nucleotide affinity toward GDP and accumulating inactive KRAS.
“Binding of compound 12 to the switch II pocket impaired KRAS signalling by shifting nucleotide affinity from favouring GTP to GDP and led to the accumulation of KRAS in its inactive state91.”
From Advances in covalent drug discovery (2022) · cites this paper as [91]
Mutant KRAS undergoes GDP-GTP cycling.
“Still, the mutant KRAS undergoes GDP–GTP cycling [5].”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cell Signaling by Receptor Tyrosine Kinases
Lemmon, M. A., & Schlessinger, J. (2010) · Cell · doi:10.1016/j.cell.2010.06.011 · Cited by 7,929 · see citing works
Comprehensive molecular profiling of lung adenocarcinoma
The Cancer Genome Atlas Research Network (2014) · Nature · doi:10.1038/nature13385 · Cited by 5,732 · see citing works
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557 · see citing works
Niesen, F., Berglund, H., & Vedadi, M. (2007) · Nature Protocols · doi:10.1038/nprot.2007.321 · Cited by 2,420 · see citing works
Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997 · see citing works
GEFs and GAPs: Critical Elements in the Control of Small G Proteins
Bos, J. L., Rehmann, H., & Wittinghofer, A. (2007) · Cell · doi:10.1016/j.cell.2007.05.018 · Cited by 1,903 · see citing works
The Guanine Nucleotide-Binding Switch in Three Dimensions
Vetter, I. R., & Wittinghofer, A. (2001) · Science · doi:10.1126/science.1062023 · Cited by 1,875 · see citing works
RAS oncogenes: weaving a tumorigenic web
Pylayeva-Gupta, Y., Grabocka, E., & Bar-Sagi, D. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3106 · Cited by 1,789 · see citing works
The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants
Scheffzek, K., Ahmadian, M. R., Kabsch, W., Wiesmüller, L., Lautwein, A., Schmitz, F., & Wittinghofer, A. (1997) · Science · doi:10.1126/science.277.5324.333 · Cited by 1,543 · see citing works
Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer
Pao, W., & Chmielecki, J. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2947 · Cited by 1,083 · see citing works
Rodriguez‐Viciana, P., Warne, P. H., Khwaja, A., Marte, B. M., Pappin, D., Das, P., Waterfield, M. D., Ridley, A. J., & Downward, J. (1997) · Cell · doi:10.1016/s0092-8674(00)80226-3 · Cited by 1,063 · see citing works
AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity
Chandarlapaty, S., Sawai, A., Scaltriti, M., Rodrik-Outmezguine, V., Grbovic-Huezo, O., Serra, V., Majumder, P. K., Baselga, J., & Rosen, N. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.10.031 · Cited by 967 · see citing works
Self-citationHuman EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene
Parada, L. F., Tabin, C. J., Shih, C., & Weinberg, R. A. (1982) · Nature · doi:10.1038/297474a0 · Cited by 947 · see citing works
The structural basis of the activation of Ras by Sos
Boriack-Sjodin, P. A., Margarit, S. M., Bar-Sagi, D., & Kuriyan, J. (1998) · Nature · doi:10.1038/28548 · Cited by 799 · see citing works
Stephen, A. G., Esposito, D., Bagni, R. K., & McCormick, F. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.017 · Cited by 795 · see citing works
Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state
Patricelli, M. P., Janes, M. R., Li, L.-S., Hansen, R., Peters, U., Kessler, L. V., Chen, Y., Kucharski, J. M., Feng, J., Ely, T., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1105 · Cited by 759 · see citing works
Self-citationActivation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change
Taparowsky, E. J., Suard, Y. M. L., Fasano, O., Shimizu, K., Goldfarb, M. P., & Wigler, M. H. (1982) · Nature · doi:10.1038/300762a0 · Cited by 703 · see citing works
Santos, E., Tronick, S. R., Aaronson, S. A., Pulciani, S., & Barbacid, M. (1982) · Nature · doi:10.1038/298343a0 · Cited by 624 · see citing works
Tumor adaptation and resistance to RAF inhibitors
Lito, P., Rosen, N., & Solit, D. B. (2013) · Nature Medicine · doi:10.1038/nm.3392 · Cited by 585 · see citing works
Self-citationLito, P., Pratilas, C. A., Joseph, E. W., Tadi, M., Halilovic, E., Zubrowski, M., Huang, A., Wong, W. L., Callahan, M. K., Merghoub, T., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.10.009 · Cited by 562 · see citing works
Self-citationMargarit, S. M., Sondermann, H., Hall, B. E., Nagar, B., Hoelz, A., Pirruccello, M., Bar‐Sagi, D., & Kuriyan, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00149-1 · Cited by 486 · see citing works
Serine and tyrosine phosphorylations cooperate in Raf‐1, but not B‐Raf activation
Mason, C., Springer, C. J., Cooper, R. G., Superti‐Furga, G., Marshall, C. J., & Marais, R. (1999) · The EMBO Journal · doi:10.1093/emboj/18.8.2137 · Cited by 459 · see citing works
EGF Receptor Signaling Is Essential for K-Ras Oncogene-Driven Pancreatic Ductal Adenocarcinoma
Navas, C., Hernández-Porras, I., Schuhmacher, A. J., Sibilia, M., Guerra, C., & Barbacid, M. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.08.001 · Cited by 391 · see citing works
Differential regulation of rasGAP and neurofibromatosis gene product activities
Bollag, G. E., & McCormick, F. P. (1991) · Nature · doi:10.1038/351576a0 · Cited by 341 · see citing works
Lito, P., Saborowski, A., Yue, J., Solomon, M., Joseph, E., Gadal, S., Saborowski, M., Kastenhuber, E., Fellmann, C., Ohara, K., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.03.011 · Cited by 324 · see citing works
Self-citationTherapeutic Strategies for Targeting Ras Proteins
Gysin, S., Salt, M. B., Young, A. E., & McCormick, F. (2011) · Genes & Cancer · doi:10.1177/1947601911412376 · Cited by 323 · see citing works
Structural Analysis of Autoinhibition in the Ras Activator Son of Sevenless
Sondermann, H., Soisson, S. M., Boykevisch, S., Yang, S., Bar‐Sagi, D., & Kuriyan, J. (2004) · Cell · doi:10.1016/j.cell.2004.10.005 · Cited by 315 · see citing works
NMR-based functional profiling of RASopathies and oncogenic RAS mutations
Smith, M. J., Neel, B. G., & Ikura, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1218173110 · Cited by 257 · see citing works
Small-molecule modulation of Ras signaling
Spiegel, J., Cromm, P. M., Zimmermann, G., Grossmann, T. N., & Waldmann, H. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1560 · Cited by 215 · see citing works
Feig, L. A., & Cooper, G. M. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.6.2472-2478.1988 · Cited by 213 · see citing works
The structural basis for the transition from Ras-GTP to Ras-GDP
Hall, B. E., Bar‐Sagi, D., & Nassar, N. N. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192453199 · Cited by 164 · see citing works
Hall, B. E., Yang, S. S., Boriack‐Sjodin, P. A., Kuriyan, J., & Bar‐Sagi, D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101727200 · Cited by 132 · see citing works
Nonradioactive determination of Ras-GTP levels using activated ras interaction assay
Taylor, S. J., Resnick, R. J., & Shalloway, D. I. (2001) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(01)33067-7 · Cited by 91 · see citing works
Comprehensive molecular profiling of lung adenocarcinoma
Lander, E. S. (2014) · DSpace@MIT (Massachusetts Institute of Technology) · Cited by 84 · see citing works
Short-Range RNA-RNA Crosslinking Methods to Determine rRNA Structure and Interactions
JUZUMIENE, D. I., Shapkina, T. G., KIRILLOV, S. V., & Wollenzien, P. L. (2001) · Methods · doi:10.1006/meth.2001.1245 · Cited by 61 · see citing works
Chin, T. M., Quinlan, M. P., Singh, A., Sequist, L. V. D., Lynch, T. J., Haber, D. A., Sharma, S. V., & Settleman, J. E. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0093 · Cited by 53 · see citing works
Alternate mechanisms of ras activation are complementary and favor and formation of ras-GTP.
Patel, G., Macdonald, M. J., Khosravi‐Far, R., Hisaka, M. M., & Der, C. J. (1992) · PubMed · Cited by 23 · see citing works
Bollag, G. E., & Zhang, C. (2013) · Nature · doi:10.1038/nature12835 · Cited by 15 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [24]Patel G MacDonald MJ Khosravi-Far R Hisaka MM Der CJ Oncogene 7 283 288 1992 1549350
Cited by
Sorted by citations
Integrated genomic characterization of pancreatic ductal adenocarcinoma
Raphael, B. J., Hruban, R. H., Aguirre, A. J., Moffitt, R. A., Yeh, J. J., Stewart, C., Robertson, A. G., Cherniack, A. D., Gupta, M., Getz, G., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.07.007 · Cited by 2,019 · see citing works
Sotorasib for Lung Cancers with <i>KRAS</i> p.G12C Mutation
Skoulidis, F., Li, B. T., Dy, G. K., Price, T. J., Falchook, G. S., Wolf, J., Italiano, A., Schuler, M., Borghaei, H., Barlesi, F., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2103695 · Cited by 1,849 · see citing works
KRAS <sup>G12C</sup> Inhibition with Sotorasib in Advanced Solid Tumors
Hong, D. S., Fakih, M. G., Strickler, J. H., Desai, J., Durm, G. A., Shapiro, G. I., Falchook, G. S., Price, T. J., Sacher, A., Denlinger, C. S., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1917239 · Cited by 1,733 · see citing works
Self-citationHallin, J., Engstrom, L. D., Hargis, L., Calinisan, A., Aranda, R., Briere, D. M., Sudhakar, N., Bowcut, V., Baer, B. R., Ballard, J. A., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1167 · Cited by 1,304 · see citing works
Self-citationAcquired Resistance to KRAS <sup>G12C</sup> Inhibition in Cancer
Awad, M. M., Liu, S., Rybkin, I. I., Arbour, K. C., Dilly, J., Zhu, V. W., Johnson, M. L., Heist, R. S., Patil, T., Riely, G. J., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2105281 · Cited by 1,247 · see citing works
Self-citationTargeting KRAS mutant cancers with a covalent G12C-specific inhibitor
Janes, M. R., Zhang, J., Li, L.-S., Hansen, R., Peters, U., Guo, X., Chen, Y., Babbar, A., Firdaus, S. J., Darjania, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.006 · Cited by 1,172 · see citing works
Self-citationKRAS Mutation: From Undruggable to Druggable in Cancer
Huang, L., Guo, Z., Wang, F., & Fu, L. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00780-4 · Cited by 1,127 · see citing works
RAS-targeted therapies: is the undruggable drugged?
Moore, A. R., Rosenberg, S. C., McCormick, F., & Malek, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0068-6 · Cited by 1,103 · see citing works
Adagrasib in Non–Small-Cell Lung Cancer Harboring a <i> KRAS <sup>G12C</sup> </i> Mutation
Jänne, P. A., Riely, G. J., Gadgeel, S. M., Heist, R. S., Ou, S.-H. I., Pacheco, J. M., Johnson, M. L., Sabari, J. K., Leventakos, K., Yau, E., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2204619 · Cited by 1,061 · see citing works
Understanding and targeting resistance mechanisms in NSCLC
Rotow, J. K., & Bivona, T. G. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.84 · Cited by 978 · see citing works
Drugging the ‘undruggable’ cancer targets
Dang, C. V., Reddy, E. P., Shokat, K. M., & Soucek, L. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.36 · Cited by 927 · see citing works
Advances in covalent drug discovery
Boike, L., Henning, N. J., & Nomura, D. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00542-z · Cited by 823 · see citing works
Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA
Coelho, M. A., de Carné Trécesson, S., Rana, S., Zecchin, D., Moore, C., Molina-Arcas, M., East, P., Spencer-Dene, B., Nye, E., Barnouin, K., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.11.016 · Cited by 653 · see citing works
Kinsey, C. G., Camolotto, S. A., Boespflug, A. M., Guillen, K. P., Foth, M., Truong, A., Schuman, S. S., Shea, J. E., Seipp, M. T., Yap, J. T., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0367-9 · Cited by 634 · see citing works
Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design
Ostrem, J. M. L., & Shokat, K. M. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.139 · Cited by 641 · see citing works
Fell, J. B., Fischer, J. P., Baer, B. R., Blake, J. F., Bouhana, K., Briere, D. M., Brown, K. D., Burgess, L. E., Burns, A. C., Burkard, M. R., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02052 · Cited by 653 · see citing works
Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition
Xue, J. Y., Zhao, Y., Aronowitz, J., Mai, T. T., Vides, A., Qeriqi, B., Kim, D., Li, C., de Stanchina, E., Mazutis, L., et al. (2020) · Nature · doi:10.1038/s41586-019-1884-x · Cited by 543 · see citing works
Self-citationThe current state of the art and future trends in RAS-targeted cancer therapies
Punekar, S. R., Velcheti, V., Neel, B. G., & Wong, K.-K. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00671-9 · Cited by 549 · see citing works
Pan-KRAS Inhibitor Disables Oncogenic Signalling and Tumour Growth
Kim, D., Herdeis, L., Rudolph, D., Zhao, Y., Böttcher, J., Vides, A., Ayala-Santos, C. I., Pourfarjam, Y., Cuevas-Navarro, A., Xue, J. Y., et al. (2023) · Nature · doi:10.1038/s41586-023-06123-3 · Cited by 534 · see citing works
Self-citationAnti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor
Hallin, J., Bowcut, V., Calinisan, A., Briere, D. M., Hargis, L., Engstrom, L. D., Laguer, J., Medwid, J., Vanderpool, D., Lifset, E., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-02007-7 · Cited by 533 · see citing works
Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated <i>KRAS</i> G12C
Yaeger, R., Weiss, J., Pelster, M. S., Spira, A. I., Barve, M., Ou, S.-H. I., Leal, T. A., Bekaii-Saab, T. S., Paweletz, C. P., Heavey, G. A., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2212419 · Cited by 527 · see citing works
EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer.
Amodio, V., Yaeger, R., Arcella, P., Cancelliere, C., Lamba, S., Lorenzato, A., Arena, S., Montone, M., Mussolin, B., Bian, Y., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0187 · Cited by 504 · see citing works
“These inhibitors can bind G12C-mutant KRAS beneath the effector binding switch II domain when KRAS is in the GDP-bound (inactive) state, trapping KRAS in its inactive form and taking advantage of the retained, intrinsic cycling of the G12C mutant from GTP-bound to GDP-bound states (7, 8).”
BackgroundSelf-citationVertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition
Ryan, M. B., Fece de la Cruz, F., Phat, S., Myers, D. T., Wong, E., Shahzade, H. A., Hong, C. B., & Corcoran, R. B. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3523 · Cited by 496 · see citing works
“Clin Cancer Res; 26(7) April 1, 2020 CLINICAL CANCER RESEARCH 1640”
BackgroundInfluentialThe MAPK and AMPK signalings: interplay and implication in targeted cancer therapy
Yuan, J., Dong, X., Yap, J., & Hu, J. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00949-4 · Cited by 500 · see citing works
New and emerging targeted treatments in advanced non-small-cell lung cancer
Hirsch, F. R., Suda, K., Wiens, J., & Bunn, P. A. (2016) · The Lancet · doi:10.1016/s0140-6736(16)31473-8 · Cited by 493 · see citing works
Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer
Zhu, G., Pei, L., Xia, H., Tang, Q., & Bi, F. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01441-4 · Cited by 482 · see citing works
Arbour, K. C., Jordan, E., Kim, H. R., Dienstag, J., Yu, H. A., Sanchez-Vega, F., Lito, P., Berger, M., Solit, D. B., Hellmann, M., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1841 · Cited by 466 · see citing works
Self-citationDiverse alterations associated with resistance to KRAS(G12C) inhibition
Zhao, Y., Murciano-Goroff, Y. R., Xue, J. Y., Ang, A., Lucas, J., Mai, T. T., Da Cruz Paula, A. F., Saiki, A. Y., Mohn, D., Achanta, P., et al. (2021) · Nature · doi:10.1038/s41586-021-04065-2 · Cited by 479 · see citing works
Self-citationImpact of a five-dimensional framework on R&D productivity at AstraZeneca
Morgan, P., Brown, D. G., Lennard, S., Anderton, M. J., Barrett, J. C., Eriksson, U. G., Fidock, M. D., Hamrén, B., Johnson, A. G., March, R. E., et al. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.244 · Cited by 457 · see citing works
Pancreatic cancer biology and genetics from an evolutionary perspective
Makohon-Moore, A. P., & Iacobuzio–Donahue, C. A. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.66 · Cited by 430 · see citing works
Nichols, R. J., Haderk, F., Stahlhut, C., Schulze, C. J., Hemmati, G., Wildes, D., Tzitzilonis, C., Mordec, K., Marquez, A., Romero, J., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0169-1 · Cited by 415 · see citing works
Therapeutic strategies to target RAS-mutant cancers
Ryan, M. B., & Corcoran, R. B. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0105-0 · Cited by 420 · see citing works
Papke, B., & Der, C. J. (2017) · Science · doi:10.1126/science.aam7622 · Cited by 399 · see citing works
Hillig, R. C., Sautier, B., Schroeder, J., Moosmayer, D., Hilpmann, A., Stegmann, C. M., Werbeck, N. D., Briem, H., Boemer, U., Weiske, J., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1812963116 · Cited by 388 · see citing works
KRAS Alleles: The Devil Is in the Detail
Haigis, K. M. (2017) · Trends in Cancer · doi:10.1016/j.trecan.2017.08.006 · Cited by 373 · see citing works
Targeting the untargetable KRAS in cancer therapy
Liu, P., Wang, Y., & Li, X. (2019) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.03.002 · Cited by 366 · see citing works
Modest, D. P., Ricard, I., Heinemann, V., Hegewisch-Becker, S., Schmiegel, W., Porschen, R., Stintzing, S., Graeven, U., Arnold, D., von Weikersthal, L. F., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw261 · Cited by 351 · see citing works
Singhal, A., Li, B. T., & O'Reilly, E. M. (2024) · Nature Medicine · doi:10.1038/s41591-024-02903-0 · Cited by 355 · see citing works
Kuljanin, M., Mitchell, D. C., Schweppe, D. K., Gikandi, A. S., Nusinow, D. P., Bulloch, N. J., Vinogradova, E. V., Wilson, D. L., Kool, E. T., Mancias, J. D., et al. (2021) · Nature Biotechnology · doi:10.1038/s41587-020-00778-3 · Cited by 305 · see citing works
CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities
Han, K., Pierce, S. E., Li, A., Spees, K., Anderson, G. R., Seoane, J. A., Lo, Y.-H., Dubreuil, M., Olivas, M., Kamber, R. A., et al. (2020) · Nature · doi:10.1038/s41586-020-2099-x · Cited by 311 · see citing works
Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants
Hofmann, M. H., Gerlach, D., Misale, S., Petronczki, M., & Kraut, N. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1331 · Cited by 336 · see citing works
Ou, S.-H. I., Jänne, P. A., Leal, T. A., Rybkin, I. I., Sabari, J. K., Barve, M. A., Bazhenova, L., Johnson, M. L., Velastegui, K. L., Cilliers, C., et al. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.21.02752 · Cited by 322 · see citing works
KRAS-Mutant non-small cell lung cancer: From biology to therapy
Ferrer, I., Zugazagoitia, J., Herbertz, S., John, W. J., Paz-Ares, L. G., & Schmid‐Bindert, G. (2018) · Lung Cancer · doi:10.1016/j.lungcan.2018.07.013 · Cited by 311 · see citing works
KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target
Román, M., Baraibar, I., López, I., Nadal, E., Rolfo, C., Vicent, S., & Gil-Bazo, I. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0789-x · Cited by 301 · see citing works
Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma
Qian, Y., Gong, Y., Fan, Z., Luo, G., Huang, Q., Deng, S., Cheng, H., Jin, K., Ni, Q., Yu, X., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00958-3 · Cited by 312 · see citing works
Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition
Wong, G. S., Zhou, J., Liu, J. B., Wu, Z., Xu, X., Li, T., Xu, D., Schumacher, S. E., Puschhof, J., McFarland, J., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0022-x · Cited by 266 · see citing works
Exploring Targeted Degradation Strategy for Oncogenic KRASG12C
Zeng, M., Xiong, Y., Safaee, N., Nowak, R. P., Donovan, K. A., Yuan, C. J., Nabet, B., Gero, T. W., Feru, F., Li, L., et al. (2020) · Cell Chemical Biology · doi:10.1016/j.chembiol.2019.12.006 · Cited by 275 · see citing works
Self-citationKRAS: From undruggable to a druggable Cancer Target
Uprety, D., & Adjei, A. A. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.102070 · Cited by 271 · see citing works
KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition
Misale, S., Fatherree, J. P., Cortez, E., Li, C., Bilton, S., Timonina, D., Myers, D. T., Lee, D., Gomez-Caraballo, M., Greenberg, M., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0368 · Cited by 259 · see citing works
Self-citationSHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
Fedele, C., Li, S., Teng, K. W., Foster, C. J. R., Peng, D., Ran, H., Mita, P., Geer, M. J., Hattori, T., Koide, A., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201414 · Cited by 265 · see citing works
Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS
Schulze, C. J., Seamon, K. J., Zhao, Y., Yang, Y. C., Cregg, J., Kim, D., Tomlinson, A., Choy, T. J., Wang, Z., Sang, B., et al. (2023) · Science · doi:10.1126/science.adg9652 · Cited by 264 · see citing works
Self-citationTargeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients
Kim, D., Xue, J. Y., & Lito, P. (2020) · Cell · doi:10.1016/j.cell.2020.09.044 · Cited by 239 · see citing works
Self-citationAdachi, Y., Ito, K., Hayashi, Y., Kimura, R., Tan, T. Z., Yamaguchi, R., & Ebi, H. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-2077 · Cited by 249 · see citing works
Emerging strategies to target RAS signaling in human cancer therapy
Chen, K., Zhang, Y., Qian, L. M., & Wang, P. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01127-w · Cited by 232 · see citing works
Ahmed, T. A., Adamopoulos, C., Karoulia, Z., Wu, X., Sachidanandam, R., Aaronson, S. A., & Poulikakos, P. I. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.013 · Cited by 214 · see citing works
The KRAS-G12C inhibitor: activity and resistance
Liu, J., Kang, R., & Tang, D. (2021) · Cancer Gene Therapy · doi:10.1038/s41417-021-00383-9 · Cited by 223 · see citing works
Jeong, W.-J., Ro, E. J., & Choi, K.-Y. (2018) · npj Precision Oncology · doi:10.1038/s41698-018-0049-y · Cited by 220 · see citing works
Ras and Rap1: A tale of two GTPases
Shah, S. K., Brock, E. J., Ji, K., & Mattingly, R. R. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.03.005 · Cited by 210 · see citing works
The pancreatic cancer genome revisited
Hayashi, A., Hong, J., & Iacobuzio-Donahue, C. A. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00463-z · Cited by 211 · see citing works
Li, F., Huang, Q., Luster, T. A., Hu, H., Zhang, H., Ng, W., Khodadadi‐Jamayran, A., Wang, W., Chen, T., Deng, J., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0780 · Cited by 201 · see citing works
Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer
Molina-Arcas, M., Moore, C., Rana, S., van Maldegem, F., Mugarza, E., Romero-Clavijo, P., Herbert, E., Horswell, S., Li, L.-S., Janes, M. R., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw7999 · Cited by 203 · see citing works
Self-citationKRAS inhibitors: resistance drivers and combinatorial strategies
Isermann, T., Sers, C., Der, C. J., & Papke, B. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.11.009 · Cited by 207 · see citing works
The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market
Titze‐de‐Almeida, R., David, C., & Titze-de-Almeida, S. S. (2017) · Pharmaceutical Research · doi:10.1007/s11095-017-2134-2 · Cited by 198 · see citing works
Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view
Lu, S., Jang, H., Gu, S., Zhang, J., & Nussinov, R. (2016) · Chemical Society Reviews · doi:10.1039/c5cs00911a · Cited by 188 · see citing works
The path to the clinic: a comprehensive review on direct KRASG12C inhibitors
Kwan, A. K., Piazza, G. A., Keeton, A. B., & Leite, C. A. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02225-w · Cited by 192 · see citing works
Survival of pancreatic cancer cells lacking KRAS function
Muzumdar, M. D., Chen, P.-Y., Dorans, K. J., Chung, K. M., Bhutkar, A., Hong, E., Noll, E. M., Sprick, M. R., Trumpp, A., & Jacks, T. (2017) · Nature Communications · doi:10.1038/s41467-017-00942-5 · Cited by 177 · see citing works
KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne?
Nagasaka, M., Li, Y., Sukari, A., Ou, S.-H. I., Al-Hallak, M. N., & Azmi, A. S. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.101974 · Cited by 185 · see citing works
RAS: Striking at the Core of the Oncogenic Circuitry
Gimple, R. C., & Wang, X. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00965 · Cited by 174 · see citing works
KRAS <sup>G12C</sup> inhibition produces a driver-limited state revealing collateral dependencies
Lou, K., Steri, V., Ge, A. Y., Hwang, Y. C., Yogodzinski, C. H., Shkedi, A. R., Choi, A. L. M., Mitchell, D. C., Swaney, D. L., Hann, B., et al. (2019) · Science Signaling · doi:10.1126/scisignal.aaw9450 · Cited by 175 · see citing works
Novel therapeutic targets on the horizon for lung cancer
Tan, W.-L., Jain, A., Takano, A. M., Newell, E. W., Iyer, N. G., Lim, W., Tan, E.-H., Zhai, W., Hillmer, A. M., Tam, W. L., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30123-1 · Cited by 184 · see citing works
Current Landscape of Targeted Therapy in Lung Cancer
Mayekar, M. K., & Bivona, T. G. (2017) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.810 · Cited by 183 · see citing works
Ross, S. J., Revenko, A. S., Hanson, L. L., Ellston, R., Staniszewska, A., Whalley, N., Pandey, S. K., Revill, M., Rooney, C., Buckett, L. K., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aal5253 · Cited by 177 · see citing works
Expanding the Armory: Predicting and Tuning Covalent Warhead Reactivity
Lonsdale, R., Burgess, J., Colclough, N., Davies, N. L., Lenz, E. M., Orton, A. L., & Ward, R. A. (2017) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.7b00553 · Cited by 190 · see citing works
KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy
Ryan, M. B., Coker, O., Sorokin, A., Fella, K., Barnes, H., Wong, E., Kanikarla, P., Gao, F., Zhang, Y., Zhou, L., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110993 · Cited by 177 · see citing works
An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer
Xue, Y., Martelotto, L., Baslan, T., Vides, A., Solomon, M., Mai, T. T., Chaudhary, N., Riely, G. J., Li, B. T., Scott, K., et al. (2017) · Nature Medicine · doi:10.1038/nm.4369 · Cited by 174 · see citing works
Self-citationMolecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer
Gu, Y., Yang, R., Zhang, Y., Guo, M., Takehiro, K., Zhan, M., Yang, L., & Wang, H. (2025) · Molecular Biomedicine · doi:10.1186/s43556-024-00239-2 · Cited by 184 · see citing works
Dy, G. K., Govindan, R., Velcheti, V., Falchook, G. S., Italiano, A., Wolf, J., Sacher, A. G., Takahashi, T., Ramalingam, S. S., Dooms, C., et al. (2023) · Journal of Clinical Oncology · doi:10.1200/jco.22.02524 · Cited by 163 · see citing works
Self-citationThe improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC)
Salgia, R., Pharaon, R. R., Mambetsariev, I., Nam, A., & Sattler, M. (2021) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100186 · Cited by 163 · see citing works
Prognostic and Predictive Value in<i>KRAS</i>in Non–Small-Cell Lung Cancer: A Review
Wood, K., Hensing, T., Malik, R., & Salgia, R. (2016) · JAMA Oncology · doi:10.1001/jamaoncol.2016.0405 · Cited by 164 · see citing works
Pharmacological targeting of RAS: recent success with direct inhibitors
O’Bryan, J. P. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2018.10.021 · Cited by 153 · see citing works
The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors
Hansen, R., Peters, U., Babbar, A., Chen, Y., Feng, J., Janes, M. R., Li, L.-S., Ren, P., Liu, Y., & Zarrinkar, P. P. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0061-5 · Cited by 153 · see citing works
Self-citationNew Treatment Strategies for Metastatic Pancreatic Ductal Adenocarcinoma
Singh, R., & O'Reilly, E. M. (2020) · Drugs · doi:10.1007/s40265-020-01304-0 · Cited by 156 · see citing works
Differential effector engagement by oncogenic KRAS
Yuan, T. L., Amzallag, A., Bagni, R., Yi, M., Afghani, S., Burgan, W., Fer, N., Strathern, L. A., Powell, K., Smith, B., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.051 · Cited by 150 · see citing works
KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge
Mao, Z., Xiao, H., Shen, P., Yang, Y., Xue, J., Yang, Y., Shang, Y., Zhang, L., Li, X., Zhang, Y., et al. (2022) · Cell Discovery · doi:10.1038/s41421-021-00368-w · Cited by 158 · see citing works
Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer
Yaeger, R., Mezzadra, R., Sinopoli, J., Bian, Y., Marasco, M., Kaplun, E., Gao, Y., Zhao, H., Paula, A. D. C., Zhu, Y., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0405 · Cited by 144 · see citing works
Self-citationRAS mutations in human cancers: Roles in precision medicine
Murugan, A. K., Grieco, M., & Tsuchida, N. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.06.007 · Cited by 146 · see citing works
Targeting the Small GTPase Superfamily through Their Regulatory Proteins
Gray, J. L., von Delft, F., & Brennan, P. E. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201900585 · Cited by 142 · see citing works
An <i>In Vivo Kras</i> Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants
Zafra, M. P., Parsons, M. J., Kim, J., Alonso-Curbelo, D., Goswami, S., Schatoff, E. M., Han, T., Katti, A., Fernandez, M. T. C., Wilkinson, J. E., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0442 · Cited by 139 · see citing works
Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C
Zeng, M., Lu, J., Li, L., Feru, F., Quan, C., Gero, T. W., Ficarro, S. B., Xiong, Y., Ambrogio, C., Paranal, R. M., et al. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.06.017 · Cited by 136 · see citing works
Self-citationA potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS
Bery, N., Miller, A., & Rabbitts, T. (2020) · Nature Communications · doi:10.1038/s41467-020-17022-w · Cited by 132 · see citing works
Cruz-Migoni, A., Canning, P., Quevedo, C. E., Bataille, C. J. R., Béry, N., Miller, A., Russell, A. J., Phillips, S. E. V., Carr, S. B., & Rabbitts, T. H. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811360116 · Cited by 135 · see citing works
Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future
Uras, I. Z., Moll, H. P., & Casanova, E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124325 · Cited by 134 · see citing works
New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness
Yang, H., Liang, S.-Q., Schmid, R. A., & Peng, R.-W. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00953 · Cited by 129 · see citing works
Targeting the Raf kinases in human cancer: the Raf dimer dilemma
Durrant, D., & Morrison, D. K. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.399 · Cited by 134 · see citing works
Lysine-Targeted Inhibitors and Chemoproteomic Probes
Cuesta, A., & Taunton, J. (2019) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044805 · Cited by 135 · see citing works
Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial
Desai, J., Alonso, G., Kim, S. H., Cervantes, A., Karasic, T., Medina, L., Shacham-Shmueli, E., Cosman, R., Falcon, A., Gort, E., et al. (2024) · Nature Medicine · doi:10.1038/s41591-023-02696-8 · Cited by 132 · see citing works
“Preclinical studies have identified EGFR as a major mediator of adaptive feedback, and concomitant blockade of EGFR has been shown to enhance the antitumor activity of KRAS G12C inhibition 12,15 .”
BackgroundMAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival
Lee, C.-S., Lee, L. C., Yuan, T. L., Chakka, S., Fellmann, C., Lowe, S. W., Caplen, N. J., McCormick, F., & Luo, J. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1817494116 · Cited by 126 · see citing works
Quevedo, C. E., Cruz-Migoni, A., Béry, N., Miller, A., Tanaka, T. U., Petch, D., Bataille, C. J. R., Lee, L. Y. W., Fallon, P. S., Tulmin, H., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05707-2 · Cited by 132 · see citing works
Targeting DNA repair pathway in cancer: Mechanisms and clinical application
Wang, M., Chen, S., & Ao, D. (2021) · MedComm · doi:10.1002/mco2.103 · Cited by 134 · see citing works
Nussinov, R., Jang, H., Tsai, C., & Cheng, F. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006658 · Cited by 129 · see citing works
- Authors
- Lito, P., Solomon, M., Li, L.-S., Hansen, R., & Rosen, N.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Wellspring Biosciences (United States) (US)
- Corresponding author
- Lito, Piro
- Rosen, Neal
- Venue
- Science
- Published
- 2016-02-05
- Volume
- 351
- Issue
- 6273
- Pages
- 604-608
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4955282
- OpenAlex
- W2233032895
- Semantic Scholar
- e165d3c03cf60d1cdc247a235e53363d62727803
- Cited by
- 691
- References
- 38
- Citations by year
- 2026: 53 · 2025: 62 · 2024: 69 · 2023: 75 · 2022: 86 · 2021: 92 · 2020: 71 · 2019: 58 · 2018: 47 · 2017: 49 · 2016: 29
- FWCI
- 31.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P01CA129243-06, K08CA191082-01A1)
- Memorial Sloan Kettering Cancer Center Experimental Therapeutics (SKI12103)
- LUNGevity Foundation Career Development Award
- V Foundation
- 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 › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12C, GTPase activity, nucleotide exchange, KRAS-driven cancers, tyrosine kinase signaling, tumor cell growth inhibition
- MeSH terms
- Adenocarcinoma of Lung, Adenocarcinoma, Alleles, Antineoplastic Agents, Azetidines, Cysteine, Cytidine Diphosphate, Enzyme Inhibitors, Glycine, Guanosine Triphosphate, Humans, Lung Neoplasms, Mutation, Piperazines, Protein Conformation, Time Factors, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, HEK293 Cells, Molecular Targeted Therapy
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
