The role of wild-type RAS in oncogenic RAS transformation

Sheffels, Erin; Kortum, Robert L.

doi:10.3390/genes12050662

Cited by 42Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesMelanoma and MAPK Pathways

The role of wild-type RAS in oncogenic RAS transformation

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Sheffels, Erin, Kortum, Robert L.·2021·Genes

DOI 10.3390/genes12050662PMC PMC8146411

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Abstract

The RAS family of oncogenes (HRAS, NRAS, and KRAS) are among the most frequently mutated protein families in cancers. RAS-mutated tumors were originally thought to proliferate independently of upstream signaling inputs, but we now know that non-mutated wild-type (WT) RAS proteins play an important role in modulating downstream effector signaling and driving therapeutic resistance in RAS-mutated cancers. This modulation is complex as different WT RAS family members have opposing functions. The protein product of the WT RAS allele of the same isoform as mutated RAS is often tumor-suppressive and lost during tumor progression. In contrast, RTK-dependent activation of the WT RAS proteins from the two non-mutated WT RAS family members is tumor-promoting. Further, rebound activation of RTK–WT RAS signaling underlies therapeutic resistance to targeted therapeutics in RAS-mutated cancers. The contributions of WT RAS to proliferation and transformation in RAS-mutated cancer cells places renewed interest in upstream signaling molecules, including the phosphatase/adaptor SHP2 and the RasGEFs SOS1 and SOS2, as potential therapeutic targets in RAS-mutated cancers.

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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 KRAS Mutants (2022) · cites this paper as [34]
Pan-KRAS inhibitors and degraders could be prime choice for cancers driven by wild-type KRAS, such as KRAS wild-type amplified or NF1 loss, and Neurofibromatosis type 1.
“Pan-KRAS inhibitors and degraders could also become the prime choice for cancers driven by wild-type KRAS, such as KRAS wild-type amplified or cancers driven by loss of the NF1 tumor suppressor, as well as Neurofibromatosis type 1 or its associated malignancies (34, 62, 63).”
From Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants (2022) · cites this paper as [34]
Several drugs targeting KRAS indirectly are currently in development by interfering with nucleotide exchange and KRAS activation via SHP2 or SOS1 inhibition.
“Several drugs targeting KRAS indirectly are currently in development by interfering with nucleotide exchange and KRAS activation via SHP2 or SOS1 inhibition [54,55,56,57,58].”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [55]

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Structural Analysis of Autoinhibition in the Ras Activator Son of Sevenless
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“RAS-GTP binding to this allosteric pocket relieves SOS1 autoinhibition [65,66], increasing SOS1 catalytic activity 80- to 500-fold [64] and activating a RAS-GTP–SOS1–WT RAS positive feedback that has been proposed to allow for ‘switch-like’ digital RAS activation [67–69].”
Background
SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models
Fedele, C., Ran, H., Diskin, B., Wei, W., Jen, J., Geer, M. J., Araki, K., Ozerdem, U., Simeone, D. M., Miller, G., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0444 · Cited by 315 · see citing works
Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3
Sun, C., Hobor, S., Bertotti, A., Zecchin, D., Huang, S., Galimi, F., Cottino, F., Prahallad, A., Grernrum, W., Tzani, A., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.02.045 · Cited by 304 · see citing works
Allosteric inhibition of SHP2: identification of a potent, selective, and orally efficacious phosphatase inhibitor
Garcia Fortanet, J., Chen, C. H.-T., Chen, Y.-N. P., Chen, Z., Deng, Z., Firestone, B., Fekkes, P., Fodor, M., Fortin, P. D., Fridrich, C., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00680 · Cited by 298 · see citing works
Wildtype Kras2 can inhibit lung carcinogenesis in mice
Zhang, Z., Wang, Y., Vikis, H. G., Johnson, L., Liu, G., Li, J., Anderson, M. W., Sills, R. C., Hong, H. L. T., Devereux, T. R., et al. (2001) · Nature Genetics · doi:10.1038/ng721 · Cited by 295 · see citing works
Polylysine and CVIM Sequences of K-RasB Dictate Specificity of Prenylation and Confer Resistance to Benzodiazepine Peptidomimetic in Vitro
James, G. L., Goldstein, J. L., & Brown, M. S. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.11.6221 · Cited by 290 · see citing works
Four Human Ras Homologs Differ in Their Abilities to Activate Raf-1, Induce Transformation, and Stimulate Cell Motility
Voice, J. K., Klemke, R. L., Le, A., & Jackson, J. H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.24.17164 · Cited by 288 · cited 2× · see citing works
“Specifically, HRAS, NRAS, and KRAS show inverse abilities to activate PI3K/AKT signaling and RAF/MEK/ERK signaling: mutant HRAS is a potent activator of PI3K but a relatively poor activator of RAF; conversely, KRAS potently activates RAF but poorly activates PI3K [78,83,84], and NRAS shows intermediate activation of b…”
Background
Inhibition of RAS function through targeting an allosteric regulatory site
Spencer-Smith, R., Koide, A., Zhou, Y., Eguchi, R. R., Sha, F., Gajwani, P., Santana, D., Gupta, A., Jacobs, M., Herrero-Garcia, E., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2231 · Cited by 283 · cited 1× · see citing works
“These data corroborated findings that mutant KRAS may act as a dimer, requiring both monomers to be activated to achieve full downstream effector engagement [46,47].”
Background
Lipid-Sorting Specificity Encoded in K-Ras Membrane Anchor Regulates Signal Output
Zhou, Y., Prakash, P., Hong, L., Cho, K., Gorfe, A. A., & Hancock, J. F. (2016) · Cell · doi:10.1016/j.cell.2016.11.059 · Cited by 283 · cited 1× · see citing works
“While the precise mechanism for differential PI3K activation between HRAS and KRAS remains unclear, a major contributor seems to be the polybasic stretch in the hypervariable region (HVR) of KRAS; mutating basic residues in the KRAS (4B) HVR inhibits RAF/MEK/ERK signaling but enhances PI3K/AKT phosphorylation [89].”
Background
Functional Specificity of Ras Isoforms: So Similar but So Different
Castellano, E., & Santos, E. (2011) · Genes & Cancer · doi:10.1177/1947601911408081 · Cited by 273 · cited 1× · see citing works
“This differential effector activation by RAS isoforms leads to the proposed model that WT RAS contributes to cancer by signaling to effectors that the mutant RAS isoform cannot activate effectively [90].”
Background
KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS
Ambrogio, C., Köhler, J., Zhou, Z.-W., Wang, H., Paranal, R., Li, J., Capelletti, M., Caffarra, C., Li, S., Lv, Q., et al. (2018) · Cell · doi:10.1016/j.cell.2017.12.020 · Cited by 270 · cited 1× · see citing works
“[29] used both mice and RASless MEFs containing floxed WT Kras, and found that removal of WT KRAS enhanced mutant KRAS-driven signaling, proliferation, and tumorigenesis.”
Method
SHP2 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
Genetic changes in skin tumor progression: Correlation between presence of a mutant ras gene and loss of heterozygosity on mouse chromosome 7
Bremner, R., & Balmain, A. (1990) · Cell · doi:10.1016/0092-8674(90)90523-h · Cited by 264 · see citing works
TAK1 Inhibition Promotes Apoptosis in KRAS-Dependent Colon Cancers
Singh, A., Sweeney, M. F., Yu, M., Burger, A., Greninger, P., Benes, C. H., Haber, D. A., & Settleman, J. (2012) · Cell · doi:10.1016/j.cell.2011.12.033 · Cited by 260 · 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
Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer
Sos, M. L., Fischer, S., Ullrich, R. T., Peifer, M., Heuckmann, J. M., Koker, M., Heynck, S., Stückrath, I., Weiss, J. M., Fischer, F., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907325106 · Cited by 255 · cited 1× · see citing works
“Combinations of MEK and PI3K/mTOR inhibitors were successful preclinically [98,109], but clinical success has been limited by toxicity [108,110,111].”
Background
Phase III Double-Blind Placebo-Controlled Study of Farnesyl Transferase Inhibitor R115777 in Patients With Refractory Advanced Colorectal Cancer
Rao, S., Cunningham, D., de Gramont, A., Scheithauer, W., Šmakal, M., Humblet, Y., Kourteva, G., Iveson, T. J., André, T., Dostalova, J., et al. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.10.037 · Cited by 244 · see citing works
Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline
Chiorean, E. G., Nandakumar, G., Fadelu, T. A., Temin, S., Alarcon-Rozas, A. E., Bejarano, S., Croitoru, A. E., Grover, S., Lohar, P. V., Odhiambo, A. O., et al. (2020) · JCO Global Oncology · doi:10.1200/jgo.19.00367 · Cited by 244 · see citing works
Negative Feedback and Adaptive Resistance to the Targeted Therapy of Cancer
Chandarlapaty, S. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0018 · Cited by 235 · see citing works
Mutant KRAS Codon 12 and 13 Alleles in Patients With Metastatic Colorectal Cancer: Assessment As Prognostic and Predictive Biomarkers of Response to Panitumumab
Peeters, M., Douillard, J.-Y., Van Cutsem, E., Siena, S., Zhang, K., Williams, R., & Wiezorek, J. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.45.1492 · Cited by 232 · see citing works
Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer
Hobbs, G. A., Baker, N. M., Miermont, A. M., Thurman, R. D., Pierobon, M., Tran, T. H., Anderson, A. O., Waters, A. M., Diehl, J. N., Papke, B., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1006 · Cited by 231 · see citing works
Oncogene Mutations, Copy Number Gains and Mutant Allele Specific Imbalance (MASI) Frequently Occur Together in Tumor Cells
Soh, J., Okumura, N., Lockwood, W. W., Yamamoto, H., Shigematsu, H., Zhang, W., Chari, R., Shames, D. S., Tang, X., MacAulay, C. E., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007464 · Cited by 227 · cited 5× · see citing works
“with decreased survival in lung cancer compared to KRAS mutations without copy number gains (LOH due to uniparental disomy or no LOH) [40].”
BackgroundInfluential
Focus on pancreas cancer
Jaffee, E. M., Hruban, R. H., Canto, M. I., & Kern, S. E. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00093-4 · Cited by 222 · cited 1× · see citing works
“KRAS is the most frequently mutated RAS family member (75% of RAS mutations), including high incidence of mutations in lung [4], colon [5], and pancreatic cancers [6], three of the top four causes of cancer-related death [2,7,8].”
Background
Oncogenic and Wild-type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling
Young, A., Lou, D., & McCormick, F. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0231 · Cited by 211 · cited 8× · see citing works
“Mechanistically, knockdown of either the mutated RAS isoform or WT RAS differentially altered basal versus RTK-stimulated effector pathway activation [50].”
BackgroundInfluential
Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers
Ebi, H., Corcoran, R. B., Singh, A., Chen, Z., Song, Y., Lifshits, E., Ryan, D. P., Meyerhardt, J. A., Benes, C., Settleman, J., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57909 · Cited by 210 · cited 7× · see citing works
“[92] showed that PI3K signaling was most often downstream of IGF-1R in KRAS-mutated colorectal cancer cells and that IGF-1R inhibition did indirectly block PI3K signaling and cooperate with MEK inhibitors to induce cell death.”
BackgroundInfluential
The origins and genetic interactions of KRAS mutations are allele- and tissue-specific
Cook, J. H., Melloni, G. E. M., Gulhan, D. C., Park, P. J., & Haigis, K. M. (2021) · Nature Communications · doi:10.1038/s41467-021-22125-z · Cited by 208 · cited 14× · see citing works
“In LUAD, 40% of KRAS mutations are G12C, whereas KRASG12C mutations occur less frequently in COAD (7%) and PAAD (1%) [8,11,14].”
BackgroundInfluential
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
Effects of Raf Dimerization and Its Inhibition on Normal and Disease-Associated Raf Signaling
Freeman, A. K., Ritt, D. A., & Morrison, D. K. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.12.018 · Cited by 201 · cited 1× · see citing works
“Upon RAS activation, RAF proteins form homo- and heterodimers, with BRAF/CRAF heterodimers being the dominant complex responsible for downstream MEK/ERK activation to promote mutant KRAS-driven transformation [88].”
Background
KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer
Burgess, M. R., Hwang, E., Mroue, R., Bielski, C. M., Wandler, A. M., Huang, B. J., Firestone, A. J., Young, A., Lacap, J. A., Crocker, L., et al. (2017) · Cell · doi:10.1016/j.cell.2017.01.020 · Cited by 183 · cited 4× · see citing works
“Increased copy number of KRAS has been corre ated with increased cell fitness in AML and CRC cells [41] and more aggressive and undifferentiated states in metastatic murine PDAC cells [45].”
BackgroundResultInfluential
HRAS mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and loss of wild‐type allele in malignancy
Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D., & Rauen, K. A. (2005) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.31078 · Cited by 180 · see citing works
Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis
Jeng, H., Taylor, L. J., & Bar‐Sagi, D. (2012) · Nature Communications · doi:10.1038/ncomms2173 · Cited by 176 · see citing works
KRAS G12C 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
Unusual Interplay of Two Types of Ras Activators, RasGRP and SOS, Establishes Sensitive and Robust Ras Activation in Lymphocytes
Roose, J. P., Mollenauer, M. N., Ho, M., Kurosaki, T., & Weiss, A. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01882-06 · Cited by 172 · cited 2× · see citing works
“For example, positive feedback activation of SOS1 by active RAS-GTP potentiates EGF signaling to downstream effectors in vitro [66] and supports prolonged RAS and ERK activation downstream of T cell and B cell receptors [75,76].”
Background
Mutational activation of the c-Ha-ras gene in liver tumors of different rodent strains: correlation with susceptibility to hepatocarcinogenesis.
Buchmann, A., Bauer-Hofmann, R., Mahr, J., Drinkwater, N. R., Luz, A., & Schwarz, M. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.3.911 · Cited by 159 · see citing works
Coordinate Direct Input of Both KRAS and IGF1 Receptor to Activation of PI3 kinase in KRAS -Mutant Lung Cancer
Molina-Arcas, M., Hancock, D. C., Sheridan, C., Kumar, M. S., & Downward, J. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0446 · Cited by 157 · cited 4× · see citing works
“Conversely, in KRAS-mutated colorectal [92] and lung [93] adenocarcinoma cells, PI3K/AKT pathway activation is dependent on RTK signaling.”
BackgroundInfluential
Treatment of Patients With Early-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline
Costas‐Chavarri, A., Nandakumar, G., Temin, S., Junior, G. L. L., Cervantes, A. M. R., Correa, M. C., Engineer, R., Hamashima, C., Ho, G. F., Huitzil-Melendez, F. D., et al. (2019) · Journal of Global Oncology · doi:10.1200/jgo.18.00214 · Cited by 157 · see citing works
H-Ras forms dimers on membrane surfaces via a protein–protein interface
Lin, W., Iversen, L., Tu, H., Rhodes, C., Christensen, S. M., Iwig, J. S., Hansen, S. D., Huang, W. Y. C., & Groves, J. T. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321155111 · Cited by 156 · see citing works
Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics
Iversen, L., Tu, H.-L., Lin, W.-C., Christensen, S. M., Abel, S. M., Iwig, J., Wu, H.-J., Gureasko, J., Rhodes, C., Petit, R. S., et al. (2014) · Science · doi:10.1126/science.1250373 · Cited by 154 · see citing works
Dual Blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) Pathways Synergistically Inhibits Rhabdomyosarcoma Cell Growth In Vitro and In Vivo
Renshaw, J., Taylor, K. R., Bishop, R. T., Valenti, M. R., Brandon, A. D. H., Gowan, S. M., Eccles, S. A., Ruddle, R. R., Johnson, L. D., Raynaud, F. I., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0850 · Cited by 152 · 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 · cited 4× · see citing works
“To broadly examine the effects of WT RAS deletion in KRAS-mutated cancer cells, we performed a meta-analysis of mutated KRAS, WT HRAS, and WT NRAS dependencies in KRAS-mutated colorectal cancer, non-small cell lung cancer, and pancreatic cancer cell lines from both the Dependency Map Portal (DepMap) [51–53] and a larg…”
BackgroundMethodInfluential
N-Ras Forms Dimers at POPC Membranes
Güldenhaupt, J., Rudack, T., Bachler, P. S., Mann, D., Triola, G., Waldmann, H., Kötting, C., & Gerwert, K. B. (2012) · Biophysical Journal · doi:10.1016/j.bpj.2012.08.043 · Cited by 148 · see citing works
MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma
Yohe, M. E., Gryder, B. E., Shern, J. F., Song, Y., Chou, H.-C., Sindiri, S., Mendoza, A., Patidar, R., Zhang, X., Guha, R., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan4470 · Cited by 148 · see citing works
Wild-Type H- and N-Ras Promote Mutant K-Ras-Driven Tumorigenesis by Modulating the DNA Damage Response
Grabocka, E., Pylayeva‐Gupta, Y., Jones, M. V., Lubkov, V., Yemanaberhan, E., Taylor, L. J., Jeng, H. H., & Bar‐Sagi, D. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.01.005 · Cited by 141 · cited 1× · see citing works
“RTK−WT RAS signaling supplements basal mutant RAS signaling to fully activate RAF/MEK/ERK and PI3K/AKT effector pathways [50,78] to promote proliferation [50] and G2 checkpoint integrity [79] in RAS-mutated cancer cells.”
Background
An In Vivo Kras 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
The role of wild type RAS isoforms in cancer
Zhou, B., Der, C. J., & Cox, A. D. (2016) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2016.07.012 · Cited by 130 · cited 2× · see citing works
“Evidence for LOH as a frequent event in cancer initiation has been observed in model systems for all three RAS genes (HRAS [23,31–34], NRAS [21,24,35], KRAS [21,36–39]).”
Background
KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis
Rabara, D., Tran, T. H., Dharmaiah, S., Stephens, R. M., McCormick, F., Simanshu, D. K., & Holderfield, M. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1908353116 · Cited by 128 · see citing works
Alternative to the soft-agar assay that permits high-throughput drug and genetic screens for cellular transformation
Rotem, A., Janzer, A., Izar, B., Ji, Z., Doench, J. G., Garraway, L. A., & Struhl, K. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505979112 · Cited by 126 · see citing works
Regulation of Ras Signaling Dynamics by Sos-Mediated Positive Feedback
Boykevisch, S., Zhao, C., Sondermann, H., Philippidou, P., Halegoua, S., Kuriyan, J., & Bar‐Sagi, D. (2006) · Current Biology · doi:10.1016/j.cub.2006.09.033 · Cited by 125 · cited 2× · see citing works
“RAS-GTP binding to this allosteric pocket relieves SOS1 autoinhibition [65,66], increasing SOS1 catalytic activity 80- to 500-fold [64] and activating a RAS-GTP–SOS1–WT RAS positive feedback that has been proposed to allow for ‘switch-like’ digital RAS activation [67–69].”
Background
Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer
Knickelbein, K., & Zhang, L. (2014) · Genes & Diseases · doi:10.1016/j.gendis.2014.10.002 · Cited by 118 · see citing works
MEK and PI3K inhibition in solid tumors: rationale and evidence to date
Jokinen, E., & Koivunen, J. P. (2015) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834015571111 · Cited by 116 · see citing works
Distinct Binding Preferences between Ras and Raf Family Members and the Impact on Oncogenic Ras Signaling
Terrell, E. M., Durrant, D., Ritt, D. A., Sealover, N. E., Sheffels, E., Spencer-Smith, R., Esposito, D., Zhou, Y., Hancock, J. F., Kortum, R. L., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.09.004 · Cited by 115 · cited 6× · see citing works
“BRAF preferentially interacts with KRAS via an interaction between the KRAS (4B) polybasic region and an acidic N-terminal region in BRAF [87].”
BackgroundInfluentialSelf-citation
RAF Suppression Synergizes with MEK Inhibition in KRAS Mutant Cancer Cells
Lamba, S., Russo, M., Sun, C., Lazzari, L., Cancelliere, C., Grernrum, W., Lieftink, C., Bernards, R., Nicolantonio, F. D., & Bardelli, A. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.033 · Cited by 109 · see citing works
Widespread Selection for Oncogenic Mutant Allele Imbalance in Cancer
Bielski, C. M., Donoghue, M. T. A., Gadiya, M. M., Hanrahan, A. J., Won, H. H., Chang, M. T., Jonsson, P., Penson, A. V., Gorelick, A. N., Harris, C., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.10.003 · Cited by 103 · cited 2× · see citing works
“KRAS MASI is associated with worse prognosis in colorectal cancer and pancreatic cancer [44] and loss of the WT KRAS allele has been found at a higher rate in metastatic KRAS-mutated lung and pancreatic cancers compared to the primary tumors [36,37].”
Background
Loss of the normal N-ras allele in a mouse thymic lymphoma induced by a chemical carcinogen.
Guerrero, I., Villasanté, A., Corces, V. G., & Pellicer, À. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.23.7810 · Cited by 99 · see citing works
Disruption of p16 and Activation of Kras in Pancreas Increase Ductal Adenocarcinoma Formation and Metastasis in vivo
Qiu, W., Sahin, F., Iacobuzio-Donahue, C. A., Garcia-Carracedo, D., Wang, W. M., Kuo, C.-Y., Chen, D., Arking, D. E., Lowy, A. M., Hruban, R. H., et al. (2011) · Oncotarget · doi:10.18632/oncotarget.357 · Cited by 99 · cited 3× · see citing works
“KRAS MASI is associated with worse prognosis in colorectal cancer and pancreatic cancer [44] and loss of the WT KRAS allele has been found at a higher rate in metastatic KRAS-mutated lung and pancreatic cancers compared to the primary tumors [36,37].”
Background
Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent manner
Wang, J., Liu, Y., Li, Z., Wang, Z., Tan, L. X., Ryu, M., Meline, B., Du, J., Young, K. H., Ranheim, E. A., et al. (2011) · Blood · doi:10.1182/blood-2010-12-326058 · Cited by 98 · cited 1× · see citing works
“Several studies have found that the WT allele corresponding to the specific mutated RAS gene (WT HRAS in HRAS-mutated cancers [22,23]; WT NRAS in NRAS-mutated cancers [24,25]; WT KRAS in KRAS-mutated cancers [23,26–30]) suppresses tumorigenesis.”
Background
Management and Future Directions in Non-Small Cell Lung Cancer with Known Activating Mutations
Gerber, D. E., Gandhi, L., & Costa, D. B. (2014) · American Society of Clinical Oncology Educational Book · doi:10.14694/edbook_am.2014.34.e353 · Cited by 88 · see citing works
Reconstructing targetable pathways in lung cancer by integrating diverse omics data
Balbin, O. A., Prensner, J. R., Sahu, A., Yocum, A. K., Shankar, S., Malik, R., Fermin, D., Dhanasekaran, S. M., Chandler, B. C., Thomas, D. G., et al. (2013) · Nature Communications · doi:10.1038/ncomms3617 · Cited by 88 · see citing works
Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis
To, M. D., Rosario, R. D., Westcott, P. M. K., Banta, K. L., & Balmain, A. (2012) · Oncogene · doi:10.1038/onc.2012.404 · Cited by 82 · cited 5× · see citing works
“(C,D) Effect of siRNA knockdown of mutant KRAS or both non-mutated WT RAS (HRAS and NRAS) genes (C) or linear correlation between mutant KRAS and WT RAS knockdown (D) from the siREN screen [23] in KRAS-mutated colorectal, NSCLC, and pancreatic cancer cell lines.”
BackgroundInfluential
Genetic Events That Limit the Efficacy of MEK and RTK Inhibitor Therapies in a Mouse Model of KRAS-Driven Pancreatic Cancer
Pettazzoni, P., Viale, A., Shah, P. K., Carugo, A., Ying, H., Wang, H., Genovese, G., Seth, S., Minelli, R., Green, T., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-1854 · Cited by 80 · cited 2× · see citing works
“RNA-sequencing studies showed that MEK inhibitor treatment induces simultaneous upregulation of multiple RTKs and ligands [113,114], so co-inhibition of individual RTKs will likely be ineffective in blocking MEK inhibitor resistance [97,104,115].”
Background
A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution
Anderson, G. R., Winter, P. S., Lin, K. H., Nussbaum, D. P., Cakir, M., Stein, E. M., Soderquist, R. S., Crawford, L., Leeds, J. C., Newcomb, R., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.006 · Cited by 80 · see citing works
Targeting the MAPK Pathway in RAS Mutant CancersPreprint
Hymowitz, S. G., & Malek, S. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031492 · Cited by 79 · see citing works
Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers
Untch, B. R., Anjos, V. D., García-Rendueles, M. E. R., Knauf, J. A., Krishnamoorthy, G. P., Saqcena, M., Bhanot, U. K., Socci, N. D., Ho, A. L., Ghossein, R. A., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-1925 · Cited by 78 · cited 3× · see citing works
“HRAS-mutated cancer cells require RTK–WT RAS signaling to activate RAF/MEK/ERK signaling [78,91].”
Background
Evidence for cell-specific differences in transformation by N-, H- and K-ras.
Maher, J., Baker, D. A., Manning, M. L., Dibb, N. J., & Roberts, I. A. G. (1995) · PubMed · Cited by 73 · see citing works
One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS
Ramharter, J., Kessler, D., Ettmayer, P., Hofmann, M. H., Gerstberger, T., Gmachl, M., Wunberg, T., Kofink, C. C., Sanderson, M. P., Arnhof, H., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01949 · Cited by 73 · see citing works
Origin of the sharp boundary that discriminates positive and negative selection of thymocytes
Prasad, A., Zikherman, J., Das, J., Roose, J. P., Weiss, A., & Chakraborty, A. K. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805981105 · Cited by 70 · see citing works
A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice
To, M. D., Pérez‐Losada, J., Mao, J., Hsu, J., Jacks, T., & Balmain, A. (2006) · Nature Genetics · doi:10.1038/ng1836 · Cited by 69 · cited 1× · see citing works
“[27] crossed the Kras2LA2 lung cancer model into different mouse strains that show differing amounts of expression from the endogenous WT Kras allele.”
Background
A systems mechanism for KRAS mutant allele–specific responses to targeted therapy
McFall, T., Diedrich, J. K., Mengistu, M., Littlechild, S. L., Paskvan, K. V., Sisk-Hackworth, L., Moresco, J. J., Shaw, A. S., & Stites, E. C. (2019) · Science Signaling · doi:10.1126/scisignal.aaw8288 · Cited by 65 · see citing works
Progress in targeting RAS with small molecule drugs
McCormick, F. P. (2019) · Biochemical Journal · doi:10.1042/bcj20170441 · Cited by 63 · cited 1× · see citing works
“While advances in targeting specific mutant RAS proteins have been made [15–18], the majority of RAS-mutated tumors remain resistant to currently available treatments [4,12,14,19,20].”
Background
NRAS Status Determines Sensitivity to SHP2 Inhibitor Combination Therapies Targeting the RAS–MAPK Pathway in Neuroblastoma
Valencia-Sama, I., Ladumor, Y., Kee, L., Adderley, T., Christopher, G., Robinson, C. M., Kano, Y., Ohh, M., & Irwin, M. S. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3822 · Cited by 62 · see citing works
One-way membrane trafficking of SOS in receptor-triggered Ras activation
Christensen, S. M., Tu, H., Jun, J. E., Alvarez, S. A., Triplet, M. G., Iwig, J. S., Yadav, K. K., Bar‐Sagi, D., Roose, J. P., & Groves, J. T. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3275 · Cited by 61 · see citing works
Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression
Woodfield, S., Zhang, L.-N., Scorsone, K. A., Liu, Y., & Zage, P. (2016) · BMC Cancer · doi:10.1186/s12885-016-2199-z · Cited by 59 · see citing works
Response to Cetuximab With or Without Irinotecan in Patients With Refractory Metastatic Colorectal Cancer Harboring the KRAS G13D Mutation: Australasian Gastro-Intestinal Trials Group ICECREAM Study
Segelov, E., Thavaneswaran, S., Waring, P. M., Desai, J., Robledo, K. P., Gebski, V., Élez, E., Nott, L. M., Karapetis, C. S., Lunke, S., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2015.65.6843 · Cited by 59 · see citing works
Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation
Sheffels, E., Sealover, N. E., Wang, C., Kim, D., Vazirani, I. A., Lee, E., Terrell, E. M., Morrison, D. K., Luo, J., & Kortum, R. L. (2018) · Science Signaling · doi:10.1126/scisignal.aar8371 · Cited by 59 · cited 2× · see citing works
“Furthermore, we showed that in KRAS-mutated cancer cells, RTK-SOS2-WT RAS signaling was necessary to provide adequate PI3K/AKT signaling for cells to survive in anchorage-independent growth conditions (protection from anoikis) [81], but HRAS- and NRAS-mutated cancer cells could survive in anchorage-independent conditi…”
BackgroundSelf-citation
LOH of chromosome 12p correlates with Kras2 mutation in non-small cell lung cancer
Li, J., Zhang, Z., Zunyan Dai, Y., Plass, C., Morris, Q., Wang, Y., Wiest, J. S., Anderson, M. W., & You, M. (2003) · Oncogene · doi:10.1038/sj.onc.1206192 · Cited by 58 · see citing works
Tipifarnib in recurrent, metastatic HRAS‐mutant salivary gland cancer
Hanna, G. J., Guenette, J. P., Chau, N. G., Sayehli, C. M., Wilhelm, C., Metcalf, R. L., Wong, D. J. L., Brose, M. S., Razaq, M., Pérez-Ruiz, E., et al. (2020) · Cancer · doi:10.1002/cncr.33036 · Cited by 55 · see citing works
Enhanced MET Translation and Signaling Sustains K-Ras–Driven Proliferation under Anchorage-Independent Growth Conditions
Fujita-Sato, S., Galeas, J., Truitt, M., Pitt, C., Urisman, A., Bandyopadhyay, S., Ruggero, D., & McCormick, F. P. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-1623 · Cited by 54 · see citing works
Knockdown of mutant K-ras expression by adenovirus-mediated siRNA inhibits the in vitro and in vivo growth of lung cancer cells
Zhang, Z., Jiang, G., Yang, F., & Wang, J. (2006) · Cancer Biology & Therapy · doi:10.4161/cbt.5.11.3297 · Cited by 54 · see citing works
Allele-specific Hras mutations and genetic alterations at tumor susceptibility loci in skin carcinomas from interspecific hybrid mice.
Nagase, H., Mao, J., & Balmain, A. (2003) · PubMed · Cited by 51 · see citing works
Deconstructing Ras Signaling in the Thymus
Kortum, R. L., Sommers, C. L., Pinski, J. M., Alexander, C. P., Merrill, R. K., Li, W., Love, P. E., & Samelson, L. E. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00317-12 · Cited by 51 · see citing works
Self-citation
KRAS mutant allele-specific imbalance in lung adenocarcinoma
Chiosea, S. I., Sherer, C., Jelic, T. M., & Đačić, S. (2011) · Modern Pathology · doi:10.1038/modpathol.2011.109 · Cited by 50 · cited 2× · see citing works
“Other surveys of both KRAS-mutated [41,42] and HRAS-mutated [43] patient tumor samples have found similar results.”
Result
The N-ras proto-oncogene can suppress the malignant phenotype in the presence or absence of its oncogene.
Díaz, R., Ahn, D. H., Lopez-Barcons, L. A., Malumbres, M., de Castro, I. P., Lue, J., Ferrer‐Miralles, N., Mangues, R., Tsong, J., Garcia, R., et al. (2002) · PubMed · Cited by 50 · see citing works
Oncogenic Ha-Ras-dependent Mitogen-activated Protein Kinase Activity Requires Signaling Through the Epidermal Growth Factor Receptor
Hamilton, M., & Wolfman, A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.43.28155 · Cited by 48 · cited 3× · see citing works
“HRAS-mutated cancer cells require RTK–WT RAS signaling to activate RAF/MEK/ERK signaling [78,91].”
Background
Transformation by HrasG12V is consistently associated with mutant allele copy gains and is reversed by farnesyl transferase inhibition
Chen, X., Makarewicz, J., Knauf, J. A., Johnson, L. K., & Fagin, J. A. (2013) · Oncogene · doi:10.1038/onc.2013.489 · Cited by 46 · cited 8× · see citing works
“Other surveys of both KRAS-mutated [41,42] and HRAS- utated [43] patient tumor samples have found similar results.”
ResultInfluential
A requirement for wild-type Ras isoforms in mutant KRas-driven signalling and transformation
Bentley, C., Jurinka, S. S., Kljavin, N. M., Vartanian, S., Ramani, S. R., Gonzalez, L. C., Yu, K., Modrusan, Z. D., Du, P., Bourgon, R., et al. (2013) · Biochemical Journal · doi:10.1042/bj20121578 · Cited by 45 · cited 4× · see citing works
“Deletion of WT HRAS lead to decreased proliferation and increased apoptosis in KRAS-mutated endometrial cancer cells [30].”
BackgroundInfluential
A Phase II Trial of Tipifarnib for Patients with Previously Treated, Metastatic Urothelial Carcinoma Harboring HRAS Mutations
Lee, H. W., Sa, J. K., Gualberto, A., Scholz, C. R., Sung, H. H., Jeong, B. C., Choi, H. Y., Kwon, G. Y., & Park, S. H. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-1246 · Cited by 44 · see citing works
Mutant allele specific imbalance in oncogenes with copy number alterations: Occurrence, mechanisms, and potential clinical implications
Yu, C.-C., Qiu, W., Juang, C. S., MANSUKHANI, M. M., Halmos, B., & Su, G. H. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.10.013 · Cited by 38 · cited 2× · see citing works
“KRAS MASI is associated with worse prognosis in colorectal cancer and pancreatic cancer [44] and loss of the WT KRAS allele has been found at a higher rate in metastatic KRAS-mutated lung and pancreatic cancers compared to the primary tumors [36,37].”
Background
Expression of the normal H-ras1 gene can suppress the transformed and tumorigenic phenotypes induced by mutant ras genes.
Spandidos, D. A., Frame, M. C., & Wilkie, N. M. (1991) · PubMed · Cited by 36 · see citing works
PDEδ Binding to Ras Isoforms Provides a Route to Proper Membrane Localization
Muratcioğlu, S., Jang, H., Gürsoy, A., Keskin, Ö., & Nussinov, R. (2017) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.7b03035 · Cited by 30 · cited 1× · see citing works
“These data corroborated findings that mutant KRAS may act as a dimer, requiring both monomers to be activated to achieve full downstream effector engagement [46,47].”
Background
Anchorage-independent growth conditions reveal a differential SOS2 dependence for transformation and survival in RAS-mutant cancer cells
Sheffels, E., Sealover, N. E., Theard, P. L., & Kortum, R. L. (2019) · Small GTPases · doi:10.1080/21541248.2019.1611168 · Cited by 30 · cited 2× · see citing works
“Furthermore, we showed that in KRAS-mutated cancer cells, RTK-SOS2-WT RAS signaling was necessary to provide adequate PI3K/AKT signaling for cells to survive in anchorage-independent growth conditions (protection from anoikis) [81], but HRAS- and NRAS-mutated cancer cells could survive in anchorage-independent conditi…”
BackgroundSelf-citation
Variation of mutant allele frequency in NRAS Q61 mutated melanomas
Hélias‐Rodzewicz, Z., Funck‐Brentano, E., Terrones, N., Beauchet, A., Zimmermann, U. S., Marin, C., Saïag, P., & Emile, J. (2017) · BMC Dermatology · doi:10.1186/s12895-017-0061-x · Cited by 29 · cited 1× · see citing works
“Evidence for LOH as a frequent event in cancer initiation has been observed in model systems for all three RAS genes (HRAS [23,31–34], NRAS [21,24,35], KRAS [21,36–39]).”
Background
Small molecule inhibitors of RAS proteins with oncogenic mutations
Orgován, Z., & Keserű, G. M. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09911-9 · Cited by 25 · cited 1× · see citing works
“While advances in targeting specific mutant RAS proteins have been made [15–18], the majority of RAS-mutated tumors remain resistant to currently available treatments [4,12,14,19,20].”
Background
Inhibition of Ras oncogenic activity by Ras protooncogenes
Diaz, R., Lue, J., Mathews, J. A., Yoon, A., Ahn, D. H., García‐España, A., Leonardi, P., Vargas, M. P., & Pellicer, À. (2004) · International Journal of Cancer · doi:10.1002/ijc.20563 · Cited by 18 · see citing works
ICECREAM: randomised phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal cancer with either KRAS, NRAS, BRAF and PI3KCA wild type, or G13D mutated tumours
Segelov, E., Waring, P. M., Desai, J., Wilson, K., Gebski, V., Thavaneswaran, S., Élez, E., Underhill, C. R., Pavlakis, N., Chantrill, L. A., et al. (2016) · BMC Cancer · doi:10.1186/s12885-016-2389-8 · Cited by 16 · see citing works
Randomized phase II study of cetuximab versus irinotecan and cetuximab in patients with chemo-refractory KRAS codon G13D metastatic colorectal cancer (G13D-study)
Nakamura, M., Aoyama, T., Ishibashi, K., Tsuji, A., Takinishi, Y., Shindo, Y., Sakamoto, J., Oba, K., & Mishima, H. (2016) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-016-3203-7 · Cited by 14 · see citing works
Preliminary Results From a Phase 2 Trial of Tipifarnib in HRAS-Mutant Head and Neck Squamous Cell Carcinomas
Ho, A. L., Chau, N. G., García, I., Ferté, C., Even, C., Burrows, F. J., Kessler, L. V., Mishra, V. S., Magnuson, K., Scholz, C. R., et al. (2018) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2017.12.156 · Cited by 8 · see citing works
Phase III Study with FOLFIRI + Cetuximab Versus FOLFIRI + Cetuximab Followed by Cetuximab Alone in RAS and BRAF WT mCRC
Pinto, C., Normanno, N., Orlandi, A., Fenizia, F., Damato, A., Maiello, E., Tamburini, E., Costanzo, F. D., Tonini, G., Bilancia, D., et al. (2018) · Future Oncology · doi:10.2217/fon-2017-0592 · Cited by 7 · see citing works
Development of Noonan syndrome by deregulation of allosteric SOS autoactivation
Umutesi, H. G., Hoang, H. M., Johnson, H. E., Nam, K., & Heo, J. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.013275 · Cited by 7 · cited 1× · see citing works
“This ‘switch-like’ behavior is important for normal childhood development [70,71], T and B cell development [72–74] and activation [75,76], and mutant KRAS-dependent cell proliferation and oncogenesis [77].”
Background
Dual Oncogenic/Anti-Oncogenic Role of PATZ1 in FRTL5 Rat Thyroid Cells Transformed by the Ha-RasV12 Oncogene
Vitiello, M., Palma, G., Monaco, M., Bello, A. M., Camorani, S., Francesca, P., Rea, D., Barbieri, A., Chiappetta, G., Vita, G. D., et al. (2019) · Genes · doi:10.3390/genes10020127 · Cited by 6 · see citing works

Flagged first, then by citations

1 of the 156 references couldn’t be matched to a known paper.

Sorted by citations

Expanding the Reach of Precision Oncology by Drugging All KRAS 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
“Pan-KRAS inhibitors and degraders could also become the prime choice for cancers driven by wild-type KRAS, such as KRAS wild-type–amplified or cancers driven by loss of the NF1 tumor suppressor, as well as neurofibromatosis type 1 or its associated malignancies (34, 62, 63).”
Background
Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways
Cháirez‐Ramírez, M. H., de la Cruz-López, K. G., & García-Carrancá, A. M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.710304 · Cited by 240 · see citing works
“These RAS-mutated cancers respond poorly to standard chemotherapy; therefore, targeted approaches need to be found (Sheffels and Kortum, 2021).”
Background
SOS2 Comes to the Fore: Differential Functionalities in Physiology and Pathology
Baltanás, F. C., García‐Navas, R., & Santos, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126613 · Cited by 32 · see citing works
Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance
Rozengurt, E., & Eibl, G. (2021) · Cancers · doi:10.3390/cancers13205126 · Cited by 30 · see citing works
“, HRAS and NRAS in a KRAS-mutated cancer) are tumor promoting in RAS-mutated tumors (reviewed in [52]).”
Background
Critical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma
Baltanás, F. C., García‐Navas, R., Rodríguez-Ramos, P., Calzada, N., Cuesta, C., Borrajo, J., Fuentes‐Mateos, R., Juan, A. O.-S., Vidaña, N., Castellano, E., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41583-1 · Cited by 26 · see citing works
“…are constitutively activated (GTP loaded) and, in theory, would not need the action of external GEF activators, various reports have shown that the cross-activation of WT RAS (which is SOS-dependent) by oncogenically mutated RAS is of critical importance for tumorigenic development 14 – 16 .”
Background
Evaluation of KRAS inhibitor-directed therapies for pancreatic cancer treatment
Long, S.-A., Amparo, A. M., Goodhart, G., Ahmad, S. A., & Waters, A. M. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1402128 · Cited by 26 · see citing works
“It has also been reported that KRAS preferentially activates the MAPK pathway whereas HRAS preferentially activates the PI3K pathway (64).”
Background
A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer
Foote, J. B., Mattox, T. E., Keeton, A. B., Chen, X., Smith, F., Berry, K. L., Holmes, T. W., Wang, J., Huang, C.-H., Ward, A., et al. (2024) · Cancer Research · doi:10.1158/0008-5472.can-24-0323 · Cited by 25 · see citing works
Cytotoxicity of combinations of the pan-KRAS SOS1 inhibitor BAY-293 against pancreatic cancer cell lines
Plangger, A., Rath, B., Stickler, S., Hochmair, M., Lang, C., Weigl, L., Funovics, M., & Hamilton, G. (2022) · Discover Oncology · doi:10.1007/s12672-022-00550-w · Cited by 25 · see citing works
“KRAS G12C is not stably locked in the GTP bound state and is still dependent on activation by upstream RTKs for GEF-mediated reloading [44, 45].”
Background
Identification of Potential Core Genes in Parkinson’s Disease Using Bioinformatics Analysis
Quan, W., Li, J., Jin, X., Liu, L., Zhang, Q., Qin, Y., Pei, X., & Chen, J. (2021) · Parkinson s Disease · doi:10.1155/2021/1690341 · Cited by 21 · see citing works
“HRAS is a member of the RAS oncogene family, and its mutations are common in a variety of cancers, including head and neck cancer, skin cancer, and hematopoietic cancers [17, 18].”
Background
SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma
Theard, P. L., Linke, A. J., Sealover, N. E., Daley, B. R., Yang, J. J., Cox, K., & Kortum, R. L. (2023) · Molecular Oncology · doi:10.1002/1878-0261.13564 · Cited by 17 · see citing works
“The RASGEFs Son of Sevenless 1 and 2 (SOS1 and SOS2) mediate RTK-stimulated RAS activation and represent common proximal RTK pathway intermediates whose inhibition has the potential to delay therapeutic resistance driven by RTK reactivation [4,20].”
BackgroundSelf-citation
A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer
Foote, J. B., Mattox, T. E., Keeton, A. B., Chen, X., Smith, F., Berry, K. L., Holmes, T., Wang, J., Huang, C.-H., Ward, A. B., et al. (2023) · doi:10.1101/2023.05.17.541233 · Cited by 13 · see citing works
SOS1 inhibitor BI-3406 shows in vivo antitumor activity akin to genetic ablation and synergizes with a KRAS G12D inhibitor in KRAS LUAD
Baltanás, F. C., Kramer‐Drauberg, M., García‐Navas, R., Patrucco, E., Petrini, E., Arnhof, H., Juan, A. O.-S., Rodríguez-Ramos, P., Borrajo-Sánchez, J., Calzada, N., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2422943122 · Cited by 16 · see citing works
KRAS, a New Target for Precision Medicine in Colorectal Cancer?
Boilève, A., Smolenschi, C., Lambert, A., Boige, V., Delaye, M., Camilleri, G. M., Tarabay, A., Valéry, M., Fuerea, A., Pudlarz, T., et al. (2024) · Cancers · doi:10.3390/cancers16203455 · Cited by 11 · see citing works
CRISPR-mediated reversion of oncogenic KRAS mutation results in increased proliferation and reveals independent roles of Ras and mTORC2 in the migration of A549 lung cancer cells
Werner, A. N., Kumar, A. I., & Charest, P. G. (2023) · Molecular Biology of the Cell · doi:10.1091/mbc.e23-05-0152 · Cited by 10 · see citing works
“These findings then add to a growing body of evidence that WT Ras proteins play critical roles in cancer, including in RAS -mutant cancers, although these roles appear to vary depending on the cellular context (Zhou et al. , 2016; Sheffels and Kortum, 2021).”
Amplification of Mutant NRAS in Melanocytic Tumors With Features of Spitz Tumors
Cloutier, J. M., Wang, M., Vemula, S. S., Mirza, S. A., Weier, J. F., Aquino, J. D., McCalmont, T. H., LeBoit, P. E., Bastian, B. C., & Yeh, I. (2024) · Modern Pathology · doi:10.1016/j.modpat.2024.100469 · Cited by 10 · see citing works
“Wildtype alleles of RAS (NRAS, KRAS, and HRAS) are known to exert tumor suppressive effects on their corresponding mutant cognate alleles 38,39 .”
Comparative Efficacy of Adagrasib and Sotorasib in KRAS G12C-Mutant NSCLC: Insights from Pivotal Trials
Peng, T., Wu, T., Yi, T.-Y., & Wu, A. (2024) · Cancers · doi:10.3390/cancers16213676 · Cited by 9 · see citing works
RAS and Other Molecular Targets in Pancreatic Cancer: The Next Wave Is Coming
Miller‐Phillips, L., & Collisson, E. A. (2023) · Current Treatment Options in Oncology · doi:10.1007/s11864-023-01096-x · Cited by 9 · see citing works
Molecular landscape of borderline ovarian tumours: A systematic review
Sadłecki, P., & Walentowicz‐Sadlecka, M. (2024) · Open Medicine · doi:10.1515/med-2024-0976 · Cited by 8 · see citing works
“The latter pathways play pivotal roles in fundamental cellular processes, such as cell polarity, proliferation, di ﬀ erentiation, adhesion, migration, and apoptosis [35].”
Background
Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds
Pallara, C., Cabot, D., Rivas, J., Brun, S., Seco, J., Abuasaker, B., Tarragó, T., Jaumot, M., Prades, R., & Agell, N. (2022) · Scientific Reports · doi:10.1038/s41598-022-19703-6 · Cited by 7 · see citing works
“Nonspecific binding was subtracted by using two linked channels (GST-KRAS minus GST).”
Method
Structural insights, regulation, and recent advances of RAS inhibitors in the MAPK signaling cascade: a medicinal chemistry perspective
Prajapati, V., Singh, A. K., Kumar, A. M., Singh, H., Pathak, P., Grishina, M., Kumar, V., Khalilullah, H., Verma, A., & Kumar, P. (2025) · RSC Medicinal Chemistry · doi:10.1039/d4md00923a · Cited by 6 · see citing works
The first embryo, the origin of cancer and animal phylogeny. I. A presentation of the neoplastic process and its connection with cell fusion and germline formation
Cofré, J., & Saalfeld, K. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1067248 · Cited by 7 · see citing works
“and future strategies for cancer treatment (Sheffels and Kortum, 2021).”
Fragment-based Drug Discovery Successful Contributions to Current Pharmacotherapeutic Agents Arsenal against Aggressive Cancers: A Mini-Review
Santos, L. M., & da Silveira, N. J. F. (2023) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520623666230714163823 · Cited by 4 · see citing works
Cooperative genomic lesions in HRAS-mutant cancers predict resistance to farnesyltransferase inhibitors
Nigam, A., Krishnamoorthy, G. P., Chatila, W. K., Berman, K., Saqcena, M., Walch, H. S., Venkatramani, M., Ho, A. L., Schultz, N. D., Fagin, J. A., et al. (2024) · Oncogene · doi:10.1038/s41388-024-03095-0 · Cited by 4 · see citing works
“Characterization and transfection of “ RASless ” mouse embryonic ﬁ broblasts”
Hematopoietic progenitor kinase 1 inhibits the development and progression of pancreatic intraepithelial neoplasia
Wang, H., Moniruzzaman, R., Li, L., Ji, B., Liu, Y., Zuo, X., Abbasgholizadeh, R., Zhao, J., Liu, G., Wang, R. L., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci163873 · Cited by 4 · see citing works
Pharmacological SOS1 inhibitor BI-3406 demonstrates in vivo anti-tumor activity comparable to SOS1 genetic ablation in KRAS mutant tumorsPreprint
Baltanás, F. C., Kramer‐Drauberg, M., García‐Navas, R., Patrucco, E., Petrini, E., Arnhof, H., Juan, A. O.-S., Rodríguez-Ramos, P., Borrajo, J., Calzada, N., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.18.613686 · Cited by 4 · see citing works
The oncogenic potential of Rab-like protein 1A (RBEL1A) GTPase: The first review of RBEL1A research with future research directions and challenges
Lui, K., Huang, Y. K., Sheikh, M. S., Cheung, K., Tam, W. Y., Sun, K.-T., Cheng, K. M., Ng, W. W. M., & Loh, A. W.-K. (2023) · Journal of Cancer · doi:10.7150/jca.84267 · Cited by 3 · see citing works
The Role of RAS in CNS Tumors: A Key Player or an Overlooked Oncogene?
Barbosa, I. D. S., Heming, C. P., Moura‐Neto, V., & Aran, V. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26094104 · Cited by 3 · see citing works
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Background
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Influential
Lactylation of Mutation-Prone RAS Residues Mimics Oncogenic Mutations and Drives Constitutive Activation
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Self-citation
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Investigatiing the Role of the Wild-Type Ras Isoforms in KRas-driven Cancer
Weyandt, J. D. (2015) · DukeSpace (Duke University)

Authors: Sheffels, E., & Kortum, R. L.
Affiliations: Uniformed Services University of the Health Sciences (US)
Corresponding author: Kortum, Robert L.
ORCID: Sheffels, Erin
Kortum, Robert L.
Venue: Genes
Publisher: MDPI AG
Published: 2021-04-28
Volume: 12
Issue: 5
Pages: 662
ISSN: 2073-4425 (ISSN-L)
DOI: 10.3390/genes12050662
PMC: PMC8146411
OpenAlex: W3158309248
Cited by: 42
References: 156
Citations by year: 2026: 3 · 2025: 8 · 2024: 12 · 2023: 12 · 2022: 3 · 2021: 4
FWCI: 0.81
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Genes (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Congressionally Directed Medical Research Programs (LC180213)
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: RAS wild-type, HRAS, NRAS, KRAS, receptor tyrosine kinase signaling, treatment resistance, SHP2, SOS1, SOS2, tumor suppression
MeSH terms: Animals, Cell Transformation, Neoplastic, Humans, ras Proteins, Drug Resistance, Neoplasm

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The role of wild-type RAS in oncogenic RAS transformation

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