An In Vivo Kras Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants
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Abstract
KRAS is the most frequently mutated oncogene in cancer, yet there is little understanding of how specific KRAS amino acid changes affect tumor initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRASG12C), pancreas (KRASG12R), and colon (KRASG13D) cancers. Induction of each allele in either the murine colon or pancreas revealed striking quantitative and qualitative differences between KRAS mutants in driving the early stages of transformation. Furthermore, using pancreatic organoid models, we show that KRASG13D mutants are sensitive to EGFR inhibition, whereas KRASG12C-mutant organoids are selectively responsive to covalent G12C inhibitors only when EGFR is suppressed. Together, these new mouse strains provide an ideal platform for investigating KRAS biology in vivo and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers. Significance: KRAS is the most frequently mutated oncogene. Here, we describe new preclinical models that mimic tissue-selective KRAS mutations and show that each mutation has distinct cellular consequences in vivo and carries differential sensitivity to targeted therapeutic agents. See related commentary by Kostyrko and Sweet-Cordero, p. 1626. This article is highlighted in the In This Issue feature, p. 1611
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Various KRAS mutation variants exhibit significant functional disparities.
“various KRAS mutation variants exhibit significant functional disparities (54)”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [54]
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Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106 · see citing works
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709 · see citing works
Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0095 · Cited by 17,455 · see citing works
Near-optimal probabilistic RNA-seq quantification
Bray, N. L., Pimentel, H., Melsted, P., & Pachter, L. (2016) · Nature Biotechnology · doi:10.1038/nbt.3519 · Cited by 9,723 · see citing works
Zehir, A., Benayed, R., Shah, R. H., Syed, A., Middha, S., Kim, H. R., Srinivasan, P., Gao, J., Chakravarty, D., Devlin, S. M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4333 · Cited by 3,380 · cited 1× · see citing works
“Specific cancer types show a clear bias in the types and frequency of KRAS alterations (1,2), and while carcinogen-specific mutational signatures define a subset of tissue-selective KRAS changes, they do not account for the majority of tissue-selective KRAS alterations (3,4).”
BackgroundHigh-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects
Kleinstiver, B. P., Pattanayak, V., Prew, M. S., Tsai, S. Q., Nguyen, N. T., Zheng, Z., & Joung, J. K. (2016) · Nature · doi:10.1038/nature16526 · Cited by 2,673 · see citing works
Hingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.023 · Cited by 2,609 · 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
Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00309-x · Cited by 2,471 · see citing works
The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumour Immunity
Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., et al. (2019) · Nature · doi:10.1038/s41586-019-1694-1 · Cited by 2,277 · see citing works
Organoid models of human and mouse ductal pancreatic cancer
Boj, S. F., Hwang, C.-I., Baker, L. A., Chio, I. I. C., Engle, D. D., Corbo, V., Jager, M., Ponz-Sarvise, M., Tiriac, H., Spector, M. S., et al. (2015) · Cell · doi:10.1016/j.cell.2014.12.021 · Cited by 2,150 · see citing works
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
Self-citationAACR Project GENIE: Powering Precision Medicine through an International Consortium
The AACR Project GENIE Consortium, The AACR Project GENIE Consortium, André, F., Arnedos, M., Baras, A. S., Baselga, J., Bedard, P. L., Berger, M. F., Bierkens, M., Calvo, F., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0151 · Cited by 1,964 · see citing works
Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-rasPreprint
Jackson, E. L., Willis, N. A., Mercer, K. L., Bronson, R. T., Crowley, D. G., Montoya, R., Jacks, T., & Tuveson, D. A. (2001) · Genes & Development · doi:10.1101/gad.943001 · Cited by 1,877 · see citing works
Pancreatitis and the Risk of Pancreatic Cancer
Lowenfels, A. B., Maisonneuve, P., Cavallini, G., Ammann, R., Lankisch, P. G., Andersen, J. R., DiMagno, E. P., Andrén‐Sandberg, Å., & Domellöf, L. (1993) · New England Journal of Medicine · doi:10.1056/nejm199305203282001 · Cited by 1,753 · see citing works
Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells
Commisso, C., Davidson, S. M., Soydaner-Azeloglu, R. G., Parker, S. J., Kamphorst, J. J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J. A., Thompson, C. B., et al. (2013) · Nature · doi:10.1038/nature12138 · Cited by 1,683 · see citing works
Hallin, 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
Guerra, C., Schuhmacher, A. J., Cañamero, M., Grippo, P. J., Verdaguer, L., Pérez-Gallego, L., Dubus, P., Sandgren, E. P., & Barbacid, M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.01.012 · Cited by 1,224 · see citing works
The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors
Kawaguchi, Y., Cooper, B., Gannon, M., Ray, M., MacDonald, R. J., & Wright, C. V. E. (2002) · Nature Genetics · doi:10.1038/ng959 · Cited by 1,007 · cited 1× · see citing works
“We analyzed the impact of each different Krasmut allele in a KrasLSL-mut/p48Cre (hereafter, KC-MUT) model whereby Cre is expressed mid-gestation and activates KRASMUT expression in almost all epithelial cells of the pancreas (14,28).”
BackgroundClinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer
Yaeger, R., Chatila, W. K., Lipsyc, M. D., Hechtman, J. F., Cercek, A., Sanchez-Vega, F., Jayakumaran, G., Middha, S., Zehir, A., Donoghue, M. T. A., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2017.12.004 · Cited by 858 · see citing works
Tuveson, D. A., Shaw, A. T., Willis, N. A., Silver, D. P., Jackson, E. L., Chang, S., Mercer, K. L., Grochow, R., Hock, H., Crowley, D., et al. (2004) · Cancer Cell · doi:10.1016/s1535-6108(04)00085-6 · Cited by 798 · see citing works
Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations
Hunter, J. C., Manandhar, A., Carrasco, M. A., Gurbani, D., Gondi, S., & Westover, K. D. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0203 · Cited by 786 · see citing works
De Roock, W., Jonker, D. J., Di Nicolantonio, F., Sartore-Bianchi, A., Tu, D., Siena, S., Lamba, S., Arena, S., Frattini, M., Piessevaux, H., et al. (2010) · JAMA · doi:10.1001/jama.2010.1535 · Cited by 748 · see citing works
Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis
Huch, M., Bonfanti, P., Boj, S., Sato, T., Loomans, C. J. M., van de Wetering, M., Sojoodi, M., Li, V. S. W., Schuijers, J., Gračanin, A., et al. (2013) · EMBO Journal · doi:10.1038/emboj.2013.204 · Cited by 710 · see citing works
An Optimized microRNA Backbone for Effective Single-Copy RNAi
Fellmann, C., Hoffmann, T., Sridhar, V., Hopfgartner, B., Muhar, M., Roth, M., Lai, D. Y., Barbosa, I. A. M., Kwon, J. S., Guan, Y., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.11.020 · Cited by 705 · see citing works
Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
Lito, P., Solomon, M., Li, L.-S., Hansen, R., & Rosen, N. (2016) · Science · doi:10.1126/science.aad6204 · Cited by 691 · 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
Haigis, K. M., Kendall, K. R., Wang, Y., Cheung, A., Haigis, M. C., Glickman, J. N., Niwa-Kawakita, M., Sweet-Cordero, A., Sebolt-Leopold, J., Shannon, K. M., et al. (2008) · Nature Genetics · doi:10.1038/ng.115 · Cited by 610 · see citing works
Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context
Guerra, C. E., Mijimolle, N., Dhawahir, A., Dubus, P. R., Barradas, M., Serrano, M., Campuzano, V., & Barbacid, M. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00191-0 · Cited by 566 · see citing works
Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS
Yao, Z., Yaeger, R., Rodrik-Outmezguine, V. S., Tao, A., Torres, N. M., Chang, M. T., Drosten, M., Zhao, H., Cecchi, F., Hembrough, T., et al. (2017) · Nature · doi:10.1038/nature23291 · Cited by 562 · see citing works
EGF Receptor is Required for KRAS-induced Pancreatic Tumorigenesis
Ardito, C. M., Grüner, B., Takeuchi, K. K., Lubeseder-Martellato, C., Teichmann, N., Mazur, P., DelGiorno, K. E., Carpenter, E. S., Halbrook, C., Hall, J. C., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.07.024 · Cited by 522 · see citing works
Kopp, J. L., Dubois, C. L., Schaffer, A., Hao, E., Shih, H., Seymour, P. A., Ma, J., & Sander, M. (2011) · Development · doi:10.1242/dev.056499 · Cited by 472 · see citing works
Morris, J. P., Cano, D., Sekine, S., Wang, S. C., & Hebrok, M. (2010) · Journal of Clinical Investigation · doi:10.1172/jci40045 · Cited by 391 · 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 · cited 1× · see citing works
“It is possible that the low oncogenicity of KRASG13D mutations in the pancreas may be driven by an increased reliance on EGFR-mediated signaling, which has a dose-dependent impact on PDAC development, even in the presence of p53 mutations (54,55).”
BackgroundKRAS 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
Eser, S., Reiff, N., Messer, M., Seidler, B., Gottschalk, K., Dobler, M., Hieber, M., Arbeiter, A., Klein, S., Kong, B., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.01.023 · Cited by 360 · see citing works
Tejpar, S., Celik, I., Schlichting, M., Sartorius, U., Bokemeyer, C., & Van Cutsem, E. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.42.2592 · Cited by 353 · see citing works
Optimized base editors enable efficient editing in cells, organoids and mice
Zafra, M. P., Schatoff, E. M., Katti, A., Foronda, M., Breinig, M., Schweitzer, A. Y., Simon, A., Han, T., Goswami, S., Montgomery, E., et al. (2018) · Nature Biotechnology · doi:10.1038/nbt.4194 · Cited by 347 · see citing works
Self-citationThe mutational landscapes of genetic and chemical models of Kras-driven lung cancer
Westcott, P. M. K., Halliwill, K. D., To, M. D., Rashid, M., Rust, A. G., Keane, T., Delrosario, R., Jen, K., Gurley, K. E., Kemp, C. J., et al. (2014) · Nature · doi:10.1038/nature13898 · Cited by 333 · see citing works
Embryonic stem cells and somatic cells differ in mutation frequency and type
Cervantes, R. B., Stringer, J. R., Shao, C., Tischfield, J. A., & Stambrook, P. J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.062527199 · Cited by 317 · see citing works
A Rapid and Scalable System for Studying Gene Function in Mice Using Conditional RNA Interference
Premsrirut, P. K., Dow, L. E., Kim, S. Y., Camiolo, M., Malone, C. D., Miething, C., Scuoppo, C., Zuber, J., Dickins, R. A., Kogan, S. C., et al. (2011) · Cell · doi:10.1016/j.cell.2011.03.012 · Cited by 315 · see citing works
Self-citationWildtype 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
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
Carrière, C., Young, A. L., Gunn, J. R., Longnecker, D. S., & Korc, M. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.03.068 · Cited by 236 · 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
Westphalen, C. B., Takemoto, Y., Tanaka, T., Macchini, M., Jiang, Z., Renz, B. W., Chen, X., Ormanns, S., Nagar, K. K., Tailor, Y. H., et al. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.03.016 · Cited by 227 · see citing works
Inducible Gene Knockouts in the Small Intestinal and Colonic Epithelium*
Saam, J., & Gordon, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.53.38071 · Cited by 211 · see citing works
Tissue-Specific Oncogenic Activity of KRASA146T
Poulin, E. J., Bera, A. K., Lu, J., Lin, Y.-J., Strasser, S. D., Paulo, J. A., Huang, T. Q., Morales, C., Yan, W., Cook, J., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1220 · Cited by 197 · see citing works
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 · see citing works
Unni, A. M., Lockwood, W. W., Zejnullahu, K., Lee-Lin, S.-Q., & VARMUS, H. E. (2015) · eLife · doi:10.7554/elife.06907 · Cited by 181 · see citing works
p21 Is a Critical CDK2 Regulator Essential for Proliferation Control in Rb-deficient Cells
Brugarolas, J., Bronson, R. T., & Jacks, T. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.141.2.503 · Cited by 153 · see citing works
Stolze, B., Reinhart, S., Bullinger, L., Fröhling, S., & Scholl, C. (2015) · Scientific Reports · doi:10.1038/srep08535 · Cited by 132 · see citing works
Baer, R., Cintas, C., Dufresne, M., Cassant-Sourdy, S., Schönhuber, N., Planque, L., Lulka, H., Couderc, B., Bousquet, C., Garmy-Susini, B., et al. (2014) · Genes & Development · doi:10.1101/gad.249409.114 · Cited by 129 · see citing works
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 · cited 2× · see citing works
“is consistent with retrospective clinical data in colorectal cancer (6,7), and two recent publications using cancer cell lines (36,37).”
BackgroundResultThe effects of mutational processes and selection on driver mutations across cancer types
Temko, D., Tomlinson, I. P. M., Severini, S., Schuster-Böckler, B., & Graham, T. A. (2018) · Nature Communications · doi:10.1038/s41467-018-04208-6 · Cited by 115 · see citing works
Dow, L. E., Nasr, Z., Saborowski, M., Ebbesen, S. H., Manchado, E., Tasdemir, N., Lee, T., Pelletier, J., & Lowe, S. W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0095236 · Cited by 112 · see citing works
Self-citationGertsenstein, M., Nutter, L. M. J., Reid, T., Pereira, M., Stanford, W. L., Rossant, J., & Nagy, A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011260 · Cited by 108 · see citing works
Winters, I. P., Chiou, S., Paulk, N. K., McFarland, C. D., Lalgudi, P. V., Ma, R. K., Lisowski, L., Connolly, A. J., Petrov, D. A., Kay, M. A., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01519-y · Cited by 93 · see citing works
Johnson, C. W., Lin, Y.-J., Reid, D., Parker, J., Pavlopoulos, S., Dischinger, P., Graveel, C., Aguirre, A. J., Steensma, M., Haigis, K. M., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.026 · Cited by 89 · see citing works
A modular and flexible ESC-based mouse model of pancreatic cancerPreprint
Saborowski, M., Saborowski, A., Morris, J. P., Bosbach, B., Dow, L. E., Pelletier, J., Klimstra, D., & Lowe, S. (2014) · Genes & Development · doi:10.1101/gad.232082.113 · Cited by 75 · see citing works
Self-citationA 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
Using the GEMM-ESC strategy to study gene function in mouse models
Huijbers, I. J., Bravo, J. D., Ali, R. B., Pritchard, C. E. J., Braumuller, T. M., van Miltenburg, M. H., Henneman, L., Michalak, E. M., Berns, A. J. M., & Jonkers, J. (2015) · Nature Protocols · doi:10.1038/nprot.2015.114 · Cited by 47 · see citing works
Immunofluorescent Staining of Mouse Intestinal Stem Cells
O’Rourke, K. P., Dow, L. E., & Lowe, S. W. (2016) · BIO-PROTOCOL · doi:10.21769/bioprotoc.1732 · Cited by 47 · see citing works
Self-citationHuijbers, I. J., Krimpenfort, P., Berns, A. J. M., & Jonkers, J. (2011) · BioEssays · doi:10.1002/bies.201100018 · Cited by 37 · see citing works
Xanthine oxidase activity in mouse pancreas: Effects of caerulein-induced acute pancreatitis
Devenyi, Z. J., Orchard, J. L., & Powers, R. E. (1987) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(87)90484-0 · Cited by 35 · see citing works
Metabolic specialization of mouse embryonic stem cells
Wang, J., Alexander, P., & McKnight, S. L. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010835 · Cited by 35 · see citing works
Reasoning in people with obsessive‐compulsive disorder
Simpson, J., Cove, J., Fineberg, N. A., Msetfi, R. M., & Ball, L. J. (2007) · British Journal of Clinical Psychology · doi:10.1348/014466507x228438 · Cited by 22 · see citing works
Chiaradonna, F., Pirola, Y., Ricciardiello, F., et al. (2016) · Genomics Data · doi:10.1016/j.gdata.2016.07.004 · Cited by 2 · see citing works
Flagged first, then by citations
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KRAS 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
The 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
Targeting 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
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 · see citing works
Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer
Tong, X., Patel, A. S., Kim, E., Li, H., Chen, Y., Li, S., Liu, S., Dilly, J., Kapner, K. S., Zhang, N., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.01.012 · Cited by 142 · see citing works
Alveolar Differentiation Drives Resistance to <i>KRAS</i> Inhibition in Lung Adenocarcinoma
Li, Z., Zhuang, X., Pan, C.-H., Yan, Y., Thummalapalli, R., Hallin, J., Torborg, S., Singhal, A., Chang, J. C., Manchado, E., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0289 · Cited by 74 · see citing works
Self-citationRecent Updates on the Significance of KRAS Mutations in Colorectal Cancer Biology
László, L., Kurilla, A., Takács, T., Kudlik, G., Koprivanacz, K., Buday, L., & Vas, V. (2021) · Cells · doi:10.3390/cells10030667 · Cited by 58 · see citing works
The role of wild-type RAS in oncogenic RAS transformation
Sheffels, E., & Kortum, R. L. (2021) · Genes · doi:10.3390/genes12050662 · Cited by 42 · see citing works
Ricciuti, B., Son, J., Okoro, J. J., Mira, A., Patrucco, E., Eum, Y., Wang, X., Paranal, R., Wang, H., Lin, M., et al. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2719 · Cited by 42 · see citing works
Diehl, A. C., Hannan, L. M., Zhen, D. B., Coveler, A. L., King, G., Cohen, S. A., Harris, W. P., Shankaran, V., Wong, K. M., Green, S., et al. (2022) · The Oncologist · doi:10.1093/oncolo/oyac179 · Cited by 35 · see citing works
Yang, W., Zhang, M., Zhang, T.-X., Liu, J.-H., Hao, M.-W., Yan, X., Gao, H., Lei, Q.-Y., Cui, J., & Zhou, X. (2024) · JCI Insight · doi:10.1172/jci.insight.178535 · Cited by 31 · see citing works
“While it may seem relatively straightforward to extrapolate the findings from KRAS G12C to KRAS G12D, we want to underline that various KRAS mutation variants exhibit significant functional disparities (54).”
- Authors
- 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., Piskounova, E., & Dow, L. E.
- Affiliations
- 1Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.
- Weill Cornell Medicine (US)
- 3Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.
- University of Washington (US)
- ORCID
- Venue
- Cancer Discovery
- Published
- 2020-11-01
- Volume
- 10
- Issue
- 11
- Pages
- 1654-1671
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC7642097
- OpenAlex
- W3048519021
- Cited by
- 139
- References
- 68
- Citations by year
- 2026: 20 · 2025: 26 · 2024: 27 · 2023: 22 · 2022: 24 · 2021: 16 · 2020: 3
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Cancer Discovery (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Repository of the University of Granada (University of Granada) (submittedVersion, other-oa)
- Funders
- NIH NCI (R01CA195787)
- NCI NIH (NIH T32 CA203702)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- KRAS, KRAS G12C, KRAS G12R, KRAS G13D, allelic series, codon 12 and 13 mutations, tumor initiation, tumor progression, pancreatic organoids, colon organoids, EGFR inhibition, targeted therapy sensitivity, lung cancer, pancreatic cancer, colon cancer
- MeSH terms
- Alleles, Humans, Oncogenes, Phenotype, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor
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