Somatic activation of the K-ras oncogene causes early onset lung cancer in mice

Johnson, Leisa; Mercer, Kim; Greenbaum, Doron; Bronson, Roderick T.; Crowley, Denise; Tuveson, David A.; Jacks, Tyler

doi:10.1038/35074129

Cited by 1,179Protein Kinase Regulation and GTPase SignalingCancer-related Molecular PathwaysCancer Genomics and Diagnostics

Somatic activation of the K-ras oncogene causes early onset lung cancer in mice

Johnson, Leisa, Mercer, Kim, Greenbaum, Doron, Bronson, Roderick T., Crowley, Denise, Tuveson, David A., Jacks, Tyler·2001·Nature

DOI 10.1038/35074129

Open this paper in CoChat — free account

Abstract

About 30% of human tumours carry ras gene mutations. Of the three genes in this family (composed of K-ras, N-ras and H-ras), K-ras is the most frequently mutated member in human tumours, including adenocarcinomas of the pancreas ( approximately 70-90% incidence), colon ( approximately 50%) and lung ( approximately 25-50%). To construct mouse tumour models involving K-ras, we used a new gene targeting procedure to create mouse strains carrying oncogenic alleles of K-ras that can be activated only on a spontaneous recombination event in the whole animal. Here we show that mice carrying these mutations were highly predisposed to a range of tumour types, predominantly early onset lung cancer. This model was further characterized by examining the effects of germline mutations in the tumour suppressor gene p53, which is known to be mutated along with K-ras in human tumours. This approach has several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers.

Integrity signals

Registry

Crossref · 10.1038/35074129

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

K-rasLA2 mice develop multi-focal lung tumors with 100% penetrance, and less frequently develop thymic lymphomas and skin papillomas.
“K-rasLA2 mice develop multi-focal lung tumors with 100% penetrance, and less frequently develop thymic lymphomas and skin papillomas (Johnson et al., 2001).”
From Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21 (2010) · cites this paper as Johnson et al., 2001
Loss of p53 or expression of dominant negative or gain-of-function Trp53 mutants co-operate with oncogenic Kras to induce LUADs with shortened latency and increased metastatic proclivity, although these tumors are less aggressive than those with Lkb1 loss.
“Loss of p53 or expression of either dominant negative or dominant gain-of-function Trp53 mutants also co-operate with oncogenic Kras to induce LUADs with shortened latency and increased metastatic proclivity, although these tumors are less aggressive than those with Lkb1 loss69–71, 84.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [69]

Genetic Alterations during Colorectal-Tumor Development
Vogelstein, B., Fearon, E. R., Hamilton, S. R., Kern, S. E., Preisinger, A. C., Leppert, M., de Vries-Smits, A. M. M., & Bos, J. L. (1988) · New England Journal of Medicine · doi:10.1056/nejm198809013190901 · Cited by 6,704 · see citing works
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · see citing works
ras oncogenes in human cancer: a review.
Bos, J. L. (1989) · PubMed · Cited by 5,061 · see citing works
Tumor spectrum analysis in p53-mutant mice
Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., & Weinberg, R. A. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00002-6 · Cited by 2,051 · see citing works
Self-citation
Prevalence of ras gene mutations in human colorectal cancers
Bos, J. L., Fearon, E. R., Hamilton, S. R., Vries, M. V., BOOM, J. H. V., van der Eb, A. J., & Vogelstein, B. (1987) · Nature · doi:10.1038/327293a0 · Cited by 1,860 · see citing works
A Dominant Mutation That Predisposes to Multiple Intestinal Neoplasia in the Mouse
Moser, A. R., Pitot, H. C., & Dove, W. F. (1990) · Science · doi:10.1126/science.2296722 · Cited by 1,591 · see citing works
Laser Capture Microdissection: Molecular Analysis of Tissue
Bonner, R. F., Emmert‐Buck, M. R., Cole, K. A., Pohida, T. J., Chuaqui, R. F., Goldstein, S. R., & Liotta, L. A. (1997) · Science · doi:10.1126/science.278.5342.1481 · Cited by 877 · see citing works
The ras gene family and human carcinogenesis
Bos, J. L. (1988) · Mutation Research/Reviews in Genetic Toxicology · doi:10.1016/0165-1110(88)90004-8 · Cited by 774 · see citing works
K-ras is an essential gene in the mouse with partial functional overlap with N-rasPreprint
Johnson, L., Greenbaum, D. C., Cichowski, K. M., Mercer, K. L., Murphy, E. A., Schmitt, E. S., Bronson, R. T., Umanoff, H., Edelmann, W., Kucherlapati, R., et al. (1997) · Genes & Development · doi:10.1101/gad.11.19.2468 · Cited by 540 · see citing works
Self-citation
Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic
Gibbs, J. B., Oliff, A. I., & Kohl, N. E. (1994) · Cell · doi:10.1016/0092-8674(94)90308-5 · Cited by 517 · see citing works
Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1
Tanaka, N., Ishihara, M., Kitagawa, M., Harada, H., Kimura, T., Matsuyama, T., Lamphier, M. S., Aizawa, S., Mak, T. W., & Taniguchi, T. (1994) · Cell · doi:10.1016/0092-8674(94)90132-5 · Cited by 491 · see citing works
Aberrant crypts: putative preneoplastic foci in human colonic mucosa.
Pretlow, T. P., Barrow, B. J., Ashton, W. S., O'Riordan, M. A., Pretlow, T. G., Jurcisek, J. A., & Stellato, T. A. (1991) · PubMed · Cited by 445 · see citing works
K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions.
Pellegata, N. S., Sessa, F., Renault, B., Bonato, M., Leone, B. E., Solcia, E., & Ranzani, G. N. (1994) · PubMed · Cited by 389 · see citing works
Alterations of myc , myb , and ras Ha Proto-Oncogenes In Cancers Are Frequent and Show Clinical Correlation
Yokota, J., Tsunetsugu‐Yokota, Y., Battifora, H. A., Fevre, C. L., & Cline, M. J. (1986) · Science · doi:10.1126/science.3941898 · Cited by 371 · see citing works
The Ras signal transduction pathway
Khosravi‐Far, R., & Der, C. J. (1994) · Cancer and Metastasis Reviews · doi:10.1007/bf00690419 · Cited by 348 · see citing works
Introduction of a subtle mutation into the Hox-2.6 locus in embryonic stem cells
Hasty, P., Ramírez‐Solis, R., Krumlauf, R. K., & Bradley, A. (1991) · Nature · doi:10.1038/350243a0 · Cited by 331 · see citing works
Transgenic Models of Tumor Development
Adams, J. M., & Cory, S. (1991) · Science · doi:10.1126/science.1957168 · Cited by 280 · see citing works
Molecular abnormalities in lung cancer.
Salgia, R., & Skarin, A. (1998) · Journal of Clinical Oncology · doi:10.1200/jco.1998.16.3.1207 · Cited by 276 · 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
[Molecular abnormalities in lung cancer].
Shimizu, S., & Mitsudomi, T. (2002) · PubMed · Cited by 235 · see citing works
Atypical Adenomatous Hyperplasia of the Lung: Implications for the Pathogenesis of Peripheral Lung Adenocarcinoma
Kitamura, H., Kameda, Y., Ito, T., et al. (1999) · American Journal of Clinical Pathology · doi:10.1093/ajcp/111.5.610 · Cited by 187 · see citing works
Increased prevalence of K-ras oncogene mutations in lung adenocarcinoma
Mills, N. E. (1995) · Lung Cancer · doi:10.1016/0169-5002(95)90161-2 · Cited by 158 · see citing works
Modeling human lung cancer in mice: similarities and shortcomings
Tuveson, D. A., & Jacks, T. (1999) · Oncogene · doi:10.1038/sj.onc.1203107 · Cited by 131 · see citing works
Self-citation
Predisposition to Neoplastic Transformation Caused by Gene Replacement of H- ras 1
Finney, R. E., & Bishop, J. M. (1993) · Science · doi:10.1126/science.8502998 · Cited by 116 · see citing works
Alveolar epithelial hyperplasia and adenocarcinoma of the lung.
Nakanishi, K. (1990) · PubMed · Cited by 90 · see citing works
Somatic and germ-line reverse mutation rates of the retrovirus-induced dilute coat-color mutation of DBA mice.
Seperack, P. K., Strobel, M. C., Corrow, D. J., et al. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.1.189 · Cited by 65 · see citing works
Atypical adenomatous hyperplasia of the lung
Montero, C. A., Gimferrer, J. M., & Belda, J. (2000) · Lung Cancer · doi:10.1016/s0169-5002(99)00135-x · Cited by 63 · see citing works
Inhibitors of prenyl transferases
Sebti, S. M., & Hamilton, A. D. (1997) · Current Opinion in Oncology · doi:10.1097/00001622-199711000-00011 · Cited by 52 · see citing works
Inhibition of Ras prenylation: a signaling target for novel anti-cancer drug design.
Lerner, E. C., Hamilton, A. D., & Sebti, S. M. (1997) · PubMed · Cited by 45 · see citing works
Expression of surfactant-associated protein in non-small-cell lung cancer: a discriminant between biologic subsets.
Linnoila, R. I., Mulshine, J. L., Steinberg, S. M., et al. (1992) · PubMed · Cited by 35 · see citing works
Mucosal IgA antibody against helicobacterpylori in chronic gastritis and intestinal metaplasia detected by the tes-tape method in resection specimens after gastrectomy for gastric cancer
Matsukura, N., Onda, M., Tokunaga, A., Matsuda, N., & Yamashita, K. (1995) · Cancer · doi:10.1002/1097-0142(19950315)75:6+ · Cited by 17 · see citing works
Differential Distribution and Increased Levels of Ras Proteins During Lung Development
Thrane, E. V., Becher, R., Låg, M., et al. (1997) · Experimental Lung Research · doi:10.3109/01902149709046046 · Cited by 16 · see citing works

Flagged first, then by citations

Sorted by citations

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
Self-citation
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043 · see citing works
RAS oncogenes: the first 30 years
Malumbres, M., & Barbacid, M. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1097 · Cited by 1,902 · 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
Hyperactive Ras in developmental disorders and cancer
Schubbert, S., Shannon, K., & Bollag, G. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2109 · Cited by 1,583 · see citing works
Ras oncogenes: split personalities
Karnoub, A. E., & Weinberg, R. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2438 · Cited by 1,467 · see citing works
Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers
Engelman, J. A., Chen, L., Tan, X., Crosby, K., Guimaraes, A. R., Upadhyay, R., Maira, M., McNamara, K., Perera, S. A., Song, Y., et al. (2008) · Nature Medicine · doi:10.1038/nm.1890 · Cited by 1,330 · see citing works
LKB1 modulates lung cancer differentiation and metastasis
Ji, H., Ramsey, M. R., Hayes, D. N., Fan, C., McNamara, K., Kozlowski, P., Torrice, C., Wu, M. C., Shimamura, T., Perera, S. A., et al. (2007) · Nature · doi:10.1038/nature06030 · Cited by 1,064 · see citing works
Self-citation
Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy
Skoulidis, F., & Heymach, J. V. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0179-8 · Cited by 1,019 · see citing works
A Gene Expression Signature Associated with “K-Ras Addiction” Reveals Regulators of EMT and Tumor Cell Survival
Singh, A., Greninger, P., Rhodes, D., Koopman, L., Violette, S., Bardeesy, N., & Settleman, J. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.03.022 · Cited by 841 · see citing works
Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects
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
Self-citation
RAS Interaction with PI3K: More Than Just Another Effector Pathway
Castellano, E., & Downward, J. (2011) · Genes & Cancer · doi:10.1177/1947601911408079 · Cited by 762 · see citing works
Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer
Davidson, S. M., Papagiannakopoulos, T., Olenchock, B. A., Heyman, J. E., Keibler, M. A., Luengo, A., Bauer, M. R., Jha, A. K., O’Brien, J. P., Pierce, K. A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.01.007 · Cited by 737 · see citing works
Self-citation
Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21
Hatley, M. E., Patrick, D. M., Garcia, M. R., Richardson, J. A., Bassel-Duby, R., van Rooij, E., & Olson, E. N. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.08.013 · Cited by 626 · see citing works
“Unlike K-ras;p53 / compound mutant mice (Johnson et al., 2001), we did not observe an increased tumor spectrum or increased metastasis in the CAGmiR-21;K-rasmutant mice.”
Influential
Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis
Guo, J. Y., Karsli-Uzunbas, G., Mathew, R., Aisner, S. C., Kamphorst, J. J., Strohecker, A. M., Chen, G., Price, S., Lu, W., Teng, X., et al. (2013) · Genes & Development · doi:10.1101/gad.219642.113 · Cited by 589 · see citing works
Self-citation
Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes
Fisher, G. H., Wellen, S. L., Klimstra, D., Lenczowski, J. M., Tichelaar, J. W., Lizak, M. J., Whitsett, J. A., Koretsky, A., & Varmus, H. E. (2001) · Genes & Development · doi:10.1101/gad.947701 · Cited by 582 · see citing works
Circadian Rhythm Disruption Promotes Lung Tumorigenesis
Papagiannakopoulos, T., Bauer, M. R., Davidson, S. M., Heimann, M., Subbaraj, L., Bhutkar, A., Bartlebaugh, J., Vander Heiden, M. G., & Jacks, T. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.07.001 · Cited by 557 · see citing works
“…validate our finding from the Cre/LoxP-based mouse model, we utilized an alternative autochthonous Kras-driven GEMM (KrasLA2/+) that gives rise to sporadic nonviral induced tumors in various tissues (e.g. lymphoma, papilloma and lung) and 100% tumor penetrance in the lung (Johnson et al., 2001).”
Self-citation
The Differential Effects of Mutant p53 Alleles on Advanced Murine Lung Cancer
Jackson, E. L., Olive, K. P., Tuveson, D. A., Bronson, R., Crowley, D., Brown, M., & Jacks, T. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-2193 · Cited by 553 · see citing works
Self-citation
Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
Brady, C. A., Jiang, D., Mello, S. S., Johnson, T. M., Jarvis, L. A., Kozak, M. M., Broz, D. K., Basak, S., Park, E. J., McLaughlin, M. E., et al. (2011) · Cell · doi:10.1016/j.cell.2011.03.035 · Cited by 533 · see citing works
Lung adenocarcinomas induced in mice by mutant EGF receptors foundin human lung cancers respondto a tyrosine kinase inhibitor orto down-regulation of the receptors
Politi, K., Zakowski, M. F., Fan, P.-D., Schonfeld, E. A., Pao, W., & Varmus, H. E. (2006) · Genes & Development · doi:10.1101/gad.1417406 · Cited by 478 · see citing works
Distinct Thresholds Govern Myc's Biological Output In Vivo
Murphy, D. J., Junttila, M. R., Pouyet, L., Karnezis, A., Shchors, K., Bui, D. A., Brown-Swigart, L., Johnson, L., & Evan, G. I. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.10.018 · Cited by 456 · see citing works
Self-citation
Tumours with PI3K activation are resistant to dietary restriction
Kalaany, N. Y., & Sabatini, D. M. (2009) · Nature · doi:10.1038/nature07782 · Cited by 468 · see citing works
An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis.
Sweet-Cordero, A., Mukherjee, S., Subramanian, A., You, H., Roix, J. J., Ladd-Acosta, C., Mesirov, J., Golub, T. R., & Jacks, T. (2005) · Nature Genetics · doi:10.1038/ng1490 · Cited by 414 · see citing works
Self-citation
A model for RAS mutation patterns in cancers: finding the sweet spot
Li, S., Balmain, A., & Counter, C. M. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0076-6 · Cited by 384 · see citing works
Downstream of Mutant KRAS, the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma
Zhang, W., Nandakumar, N., Shi, Y., Manzano, M., Smith, A., Graham, G., Gupta, S., Vietsch, E. E., Laughlin, S. Z., Wadhwa, M., et al. (2014) · Science Signaling · doi:10.1126/scisignal.2005049 · Cited by 360 · see citing works
LC3-Associated Phagocytosis in Myeloid Cells Promotes Tumor Immune Tolerance
Cunha, L. D., Yang, M., Carter, R., Guy, C., Harris, L., Crawford, J. C., Quarato, G., Boada-Romero, E., Kalkavan, H., Johnson, M. D. L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.061 · Cited by 334 · see citing works
Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches
Reck, M., Carbone, D. P., Garassino, M., & Barlesi, F. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.06.001 · Cited by 326 · see citing works
Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder
Braun, B. S., Tuveson, D. A., Kong, N., Le, D. T., Kogan, S. C., Rozmus, J., Le Beau, M. M., Jacks, T. E., & Shannon, K. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307203101 · Cited by 299 · see citing works
Self-citation
c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma
Blasco, R. B., Francoz, S., Santamaría, D., Cañamero, M., Dubus, P., Charron, J., Baccarini, M., & Barbacid, M. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.04.002 · Cited by 302 · see citing works
Deficiencies in Mouse Myh and Ogg1 Result in Tumor Predisposition and G to T Mutations in Codon 12 of the K-Ras Oncogene in Lung Tumors
Xie, Y., Yang, H., Cunanan, C., Okamoto, K., Shibata, D., Pan, J., Barnes, D. E., Lindahl, T., McIlhatton, M., Fishel, R., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-3834 · Cited by 291 · see citing works
Spatial genomics enables multi-modal study of clonal heterogeneity in tissues
Zhao, T., Chiang, Z. D., Morriss, J. W., LaFave, L. M., Murray, E. M., Del Priore, I., Meli, K., Lareau, C. A., Nadaf, N. M., Li, J., et al. (2022) · Nature · doi:10.1038/s41586-021-04217-4 · Cited by 268 · see citing works
Self-citation
Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease
Chan, I. T., Kutok, J. L., Williams, I. R., Cohen, S., Kelly, L., Shigematsu, H., Johnson, L., Akashi, K., Tuveson, D. A., Jacks, T., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20476 · Cited by 270 · see citing works
Self-citation
Smoking, p53 Mutation, and Lung Cancer
Gibbons, D. L., Byers, L. A., & Kurie, J. M. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0539 · Cited by 255 · see citing works
Lung adenocarcinoma distally rewires hepatic circadian homeostasis
Masri, S., Papagiannakopoulos, T., Kinouchi, K., Liu, Y., Cervantes, M., Baldi, P., Jacks, T., & Sassone-Corsi, P. (2016) · Cell · doi:10.1016/j.cell.2016.04.039 · Cited by 234 · see citing works
Self-citation
Senescent alveolar macrophages promote early-stage lung tumorigenesis
Prieto, L. I., Sturmlechner, I., Graves, S. I., Zhang, C., Goplen, N. P., Yi, E. S., Sun, J., Li, H., & Baker, D. J. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.05.006 · Cited by 212 · 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
Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth
Sangodkar, J., Perl, A., Tohme, R., Kiselar, J., Kastrinsky, D. B., Zaware, N., Izadmehr, S., Mazhar, S., Wiredja, D. D., O’Connor, C. M., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci89548 · Cited by 196 · 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
Glucocorticoid-induced tumor necrosis factor receptor–related protein co-stimulation facilitates tumor regression by inducing IL-9–producing helper T cells
Kim, I.-K., Kim, B.-S., Koh, C.-H., Seok, J.-W., Park, J.-S., Shin, K.-S., Bae, E.-A., Lee, G.-E., Jeon, H., Cho, J., et al. (2015) · Nature Medicine · doi:10.1038/nm.3922 · Cited by 167 · see citing works
Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma
Chung, K. M., Singh, J., Lawres, L., Dorans, K. J., Garcia, C., Burkhardt, D. B., Robbins, R., Bhutkar, A., Cardone, R., Zhao, X., et al. (2020) · Cell · doi:10.1016/j.cell.2020.03.062 · Cited by 150 · see citing works
Self-citation
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 · see citing works
Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma
Yu, Y., Schleich, K., Yue, B., Ji, S., Lohneis, P., Kemper, K., Silvis, M. R., Qutob, N., van Rooijen, E., Werner-Klein, M., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.01.002 · Cited by 156 · see citing works
RAS 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
HIF2α cooperates with RAS to promote lung tumorigenesis in mice
Kim, W. Y., Perera, S., Zhou, B., Carretero, J., Yeh, J. J., Heathcote, S. A., Jackson, A. L., Nikolinakos, P., Ospina, B., Naumov, G., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38443 · Cited by 141 · see citing works
TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis
Zhu, L., Li, Y., Xie, X., Zhou, X., Gu, M., Jie, Z., Ko, C.-J., Gao, T., Hernandez, B. E., Cheng, X., et al. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0429-8 · Cited by 109 · see citing works
Sprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis
Shaw, A. T., Meissner, A., Dowdle, J. A., Crowley, D., Magendantz, M., Ouyang, C., Parisi, T., Rajagopal, J., Blank, L. J., Bronson, R. T., et al. (2007) · Genes & Development · doi:10.1101/gad.1526207 · Cited by 131 · see citing works
Self-citation
LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma
Liu, W., Monahan, K. B., Pfefferle, A. D., Shimamura, T., Sorrentino, J., Chan, K. T., Roadcap, D. W., Ollila, D. W., Thomas, N. E., Castrillon, D. H., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.03.048 · Cited by 127 · see citing works
Physiologic functions of PP2A: Lessons from genetically modified mice
Reynhout, S., & Janssens, V. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.07.010 · Cited by 124 · see citing works
The genetics and biology of KRAS in lung cancer
Westcott, P. M. K., & To, M. D. (2013) · Chinese Journal of Cancer · doi:10.5732/cjc.012.10098 · Cited by 116 · see citing works
Focal Adhesion Kinase Regulates the DNA Damage Response and Its Inhibition Radiosensitizes Mutant KRAS Lung Cancer
Tang, K.-J., Constanzo, J. D., Venkateswaran, N., Melegari, M., Ilcheva, M., Morales, J. C., Skoulidis, F., Heymach, J. V., Boothman, D. A., & Scaglioni, P. P. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2603 · Cited by 91 · see citing works
Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
Tang, D., Kroemer, G., & Kang, R. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01422-7 · Cited by 80 · see citing works
RAS Mutations and Oncogenesis: Not all RAS Mutations are Created Equally
Miller, M. S., & Miller, L. D. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2011.00100 · Cited by 76 · see citing works
Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers
Muzumdar, M. D., Dorans, K. J., Chung, K. M., Robbins, R., Tammela, T., Gocheva, V., Li, C. M.-C., & Jacks, T. (2016) · Nature Communications · doi:10.1038/ncomms12685 · Cited by 72 · see citing works
Self-citation
c-Jun N-Terminal Kinase Contributes to Aberrant Retinoid Signaling in Lung Cancer Cells by Phosphorylating and Inducing Proteasomal Degradation of Retinoic Acid Receptor α
Srinivas, H., Juroske, D. M., Kalyankrishna, S., Cody, D. D., Price, R. E., Xu, X.-C., Narayanan, R., Weigel, N. L., & Kurie, J. M. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.3.1054-1069.2005 · Cited by 68 · see citing works
Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance
Thatikonda, V., Lyu, H., Jurado, S., Kostyrko, K., Bristow, C. A., Albrecht, C., Alpar, D., Arnhof, H., Bergner, O., Bosch, K., et al. (2024) · Nature Cancer · doi:10.1038/s43018-024-00800-6 · Cited by 76 · see citing works
Pre-clinical Models of Metastasis in Pancreatic Cancer
Miquel, M., Zhang, S., & Pilarsky, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.748631 · Cited by 53 · see citing works
Comparison of gene expression and DNA copy number changes in a murine model of lung cancer
Sweet‐Cordero, A., Tseng, G. C., You, H., Douglass, M., Huey, B., Albertson, D., & Jacks, T. (2006) · Genes, Chromosomes and Cancer · doi:10.1002/gcc.20296 · Cited by 45 · see citing works
Self-citation
Identification of a new inhibitor of KRAS‐PDEδ interaction targeting KRAS mutant nonsmall cell lung cancer
Leung, E. L., Luo, L. X., Li, Y., Liu, Z., Li, L. L., Shi, D. F., Xie, Y., Huang, M., Lu, L. L., Duan, F. G., et al. (2019) · International Journal of Cancer · doi:10.1002/ijc.32222 · Cited by 39 · see citing works
Single Copies of Mutant KRAS and Mutant PIK3CA Cooperate in Immortalized Human Epithelial Cells to Induce Tumor Formation
Wang, G. M., Wong, H. Y., Konishi, H., Blair, B. G., Abukhdeir, A. M., Gustin, J. P., Rosen, D. M., Denmeade, S. R., Rasheed, Z., Matsui, W., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-1578 · Cited by 39 · see citing works
RAS Mutations Are Not Created Equal
Hobbs, G. A., & Der, C. J. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0406 · Cited by 35 · see citing works
Genetic Modification of the Lung Directed Toward Treatment of Human Disease
Sondhi, D., Stiles, K. M., De, B. P., & Crystal, R. G. (2017) · Human Gene Therapy · doi:10.1089/hum.2016.152 · Cited by 36 · see citing works
Combined subcarcinogenic benzo[a]pyrene and UVA synergistically caused high tumor incidence and mutations in H‐ras gene, but not p53, in SKH‐1 hairless mouse skin
Wang, Y., Gao, D., Atencio, D. P., Perez, E., Saladi, R., Moore, J., Guevara, D., Rosenstein, B. S., Lebwohl, M., & Wei, H. (2005) · International Journal of Cancer · doi:10.1002/ijc.21039 · Cited by 35 · see citing works
Effect of cyclical intermittent hypoxia on Ad5CMVCre induced solitary lung cancer progression and spontaneous metastases in the KrasG12D+; p53fl/fl; myristolated p110fl/fl ROSA-gfp mouse
Guo, X., Liu, Y., Kim, J. L., Kim, E. Y., Kim, E. Q., Jansen, A., Li, K., Chan, M., Keenan, B. T., Conejo-Garcia, J., et al. (2019) · PLOS ONE · doi:10.1371/journal.pone.0212930 · Cited by 23 · see citing works
Natural killer cells limit the clearance of senescent lung adenocarcinoma cells
Stokes, K. L., Cortez-Retamozo, V., Acosta, J., Lauderback, B., Robles-Oteiza, C., Cicchini, M., Pittet, M. J., & Feldser, D. M. (2019) · Oncogenesis · doi:10.1038/s41389-019-0133-3 · Cited by 21 · see citing works
Smoking history and lung carcinoma: KRAS mutation is an early hit in lung adenocarcinoma development
Thunnissen, F. B., Prinsen, C., Hol, B., Van der Drift, M., Vesin, A., Brambilla, C., Montuenga, L., & Field, J. K. (2012) · Lung Cancer · doi:10.1016/j.lungcan.2011.07.013 · Cited by 19 · see citing works
Dicer1 phosphomimetic promotes tumor progression and dissemination
Aryal, N. K., Pant, V., Wasylishen, A. R., Rimel, B. J., Baseler, L., El-Naggar, A. K., Mutch, D. G., Goodfellow, P. J., Arur, S., & Lozano, G. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2460 · Cited by 17 · see citing works
K‐<scp>RasV14I</scp>‐induced Noonan syndrome predisposes to tumour development in mice
Hernández‐Porras, I., Schuhmacher, A. J., Garcia‐Medina, R., Jiménez, B., Cañamero, M., de Martino, A., & Guerra, C. (2016) · The Journal of Pathology · doi:10.1002/path.4719 · Cited by 16 · see citing works
Novel Compound 1, 3-bis (3, 5-dichlorophenyl) urea Inhibits Lung Cancer Progression
Singhal, S. S., Figarola, J., Singhal, J., Nagaprashantha, L., Berz, D., Rahbar, S., & Awasthi, S. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.09.022 · Cited by 14 · see citing works
Targeting PP2A in cancer: an underrated option
Sarais, F., Krempien, F., Koehn, C., Brewing, L., Classen, C. F., Walter, M., & Shokraie, O. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03560-y · Cited by 8 · see citing works

The mutational landscape of human somatic and germline cells
Moore, L., Cagan, A., Coorens, T. H. H., Neville, M. D. C., Sanghvi, R., Sanders, M. A., Oliver, T. R. W., Leongamornlert, D. A., Ellis, P., Noorani, A., et al. (2022) · Yearbook of pediatric endocrinology · doi:10.1101/2020.11.25.398172 · Cited by 55 · see citing works
Differences between germline and somatic mutation rates in humans and mice
Milholland, B., Dong, X., Zhang, L., Hao, X., Suh, Y., & Vijg, J. (2017) · Nature Communications · doi:10.1038/ncomms15183 · Cited by 423 · see citing works
Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan
Zbar, B., Kishida, T., Chen, F., Schmidt, L. S., Maher, E. R., Richards, F. M., Crossey, P. A., Webster, A. R., Affara, N. A., Ferguson-Smith, M. A., et al. (1996) · Human Mutation · doi:10.1002/(sici)1098-1004(1996)8:4 · Cited by 503 · see citing works
28. Identification of TP53 germline variants in pediatric patients undergoing tumor testing
Luo, M., MacFarland, S. P., Zelley, K., et al. (2022) · Cancer Genetics · doi:10.1016/j.cancergen.2021.05.042
Simultaneous Adrenocortical Carcinoma and Neuroblastoma in an Infant With a Novel Germline p53 Mutation
Courtney, R., & Ranganathan, S. (2014) · Journal of Pediatric Hematology/Oncology · doi:10.1097/mph.0000000000000281 · Cited by 10 · see citing works

Authors: Johnson, L., Mercer, K., Greenbaum, D., Bronson, R. T., Crowley, D., Tuveson, D. A., & Jacks, T.
Affiliations: Massachusetts Institute of Technology (US)
Howard Hughes Medical Institute (US)
University of California, San Francisco (US)
Tufts University (US)
Corresponding author: Jacks, Tyler
ORCID: Mercer, Kim
Bronson, Roderick T.
Tuveson, David A.
Jacks, Tyler
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2001-04-26
Volume: 410
Issue: 6832
Pages: 1111-1116
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/35074129
OpenAlex: W1611210979
Cited by: 1,179
References: 32
Citations by year: 2026: 17 · 2025: 33 · 2024: 36 · 2023: 47 · 2022: 30 · 2021: 57 · 2020: 47 · 2019: 49 · 2018: 41 · 2017: 54 · 2016: 46 · 2015: 52 · 2014: 52 · 2013: 59 · 2012: 61
FWCI: 13.64
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders: Howard Hughes Medical Institute
National Institutes of Health
National Cancer Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: K-ras oncogene, early-onset lung cancer, mouse tumor model, gene targeting, spontaneous recombination, germline mutations, lung adenocarcinoma
MeSH terms: Alleles, Animals, Cell Line, Disease Models, Animal, Gene Expression Regulation, Humans, Lung Neoplasms, Lymphoma, Mice, Inbred C57BL, Mutation, Papilloma, Genes, ras, Recombination, Genetic, Skin Neoplasms, Thymus Neoplasms, Genes, p53, Gene Targeting, Mice

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

Somatic activation of the K-ras oncogene causes early onset lung cancer in mice

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks