Overview of KRAS‐Driven Genetically Engineered Mouse Models of Non‐Small Cell Lung Cancer

Clare Sheridan1, Julian Downward2

1 Signal Transduction Laboratory, The Francis Crick Institute, London, 2 Lung Cancer Group, The Institute of Cancer Research, London
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 14.35
DOI:  10.1002/0471141755.ph1435s70
Online Posting Date:  September, 2015
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library


KRAS, the most frequently mutated oncogene in non‐small cell lung cancer, has been utilized extensively to model human lung adenocarcinomas. The results from such studies have enhanced considerably an understanding of the relationship between KRAS and the development of lung cancer. Detailed in this overview are the features of various KRAS‐driven genetically engineered mouse models (GEMMs) of non‐small cell lung cancer, their utilization, and the potential of these models for the study of lung cancer biology. © 2015 by John Wiley & Sons, Inc.

Keywords: mouse models; lung cancer; KRAS; non‐small cell lung cancer; p53

PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • KrasLA2 Spontaneous Model of Lung Cancer
  • KrasLSL Conditional Models of Temporally Controlled Lung Cancer
  • Inducible and Reversible Lung Cancer Models with Transgenic Expression of Kras
  • Models for Investigating Tumor Maintenance and Tumor‐Host Interactions
  • Conclusions
  • Acknowledgements
  • Literature Cited
  • Figures
  • Tables
PDF or HTML at Wiley Online Library


PDF or HTML at Wiley Online Library



Literature Cited

Literature Cited
  Ahn, Y.H., Yang, Y., Gibbons, D.L., Creighton, C.J., Yang, F., Wistuba, II, Lin, W., Thilaganathan, N., Alvarez, C.A., Roybal, J., Goldsmith, E.J., Tournier, C., and Kurie, J.M. 2011. Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator‐activated receptor gamma2 expression. Mol. Cell. Biol. 31:4270‐4285.
  Barbie, D.A., Tamayo, P., Boehm, J.S., Kim, S.Y., Moody, S.E., Dunn, I.F., Schinzel, A.C., Sandy, P., Meylan, E., Scholl, C., Frohling, S., Chan, E.M., Sos, M.L., Michel, K., Mermel, C., Silver, S.J., Weir, B.A., Reiling, J.H., Sheng, Q., Gupta, P.B., Wadlow, R.C., Le, H., Hoersch, S., Wittner, B.S., Ramaswamy, S., Livingston, D.M., Sabatini, D.M., Meyerson, M., Thomas, R.K., Lander, E.S., Mesirov, J.P., Root, D.E., Gilliland, D.G., Jacks, T., and Hahn, W.C. 2009. Systematic RNA interference reveals that oncogenic KRAS‐driven cancers require TBK1. Nature 462:108‐112.
  Basseres, D.S., Ebbs, A., Cogswell, P.C., and Baldwin, A.S. 2014. IKK is a therapeutic target in KRAS‐Induced lung cancer with disrupted p53 activity. Genes Cancer 5:41‐55.
  Blasco, R.B., Francoz, S., Santamaria, D., Canamero, M., Dubus, P., Charron, J., Baccarini, M., and Barbacid, M. 2011. c‐Raf, but not B‐Raf, is essential for development of K‐Ras oncogene‐driven non‐small cell lung carcinoma. Cancer Cell 19:652‐663.
  Bouabe, H. and Okkenhaug, K. 2013. Gene targeting in mice: A review. Methods Mol. Biol. 1064:315‐336.
  Castellano, E., Sheridan, C., Thin, M.Z., Nye, E., Spencer‐Dene, B., Diefenbacher, M.E., Moore, C., Kumar, M.S., Murillo, M.M., Gronroos, E., Lassailly, F., Stamp, G., and Downward, J. 2013. Requirement for interaction of PI3‐kinase p110alpha with RAS in lung tumor maintenance. Cancer Cell 24:617‐630.
  Cellurale, C., Sabio, G., Kennedy, N.J., Das, M., Barlow, M., Sandy, P., Jacks, T., and Davis, R.J. 2011. Requirement of c‐Jun NH(2)‐terminal kinase for Ras‐initiated tumor formation. Mol. Cell. Biol. 31:1565‐1576.
  Champiat, S., Ferte, C., Lebel‐Binay, S., Eggermont, A., and Soria, J.C. 2014. Exomics and immunogenics: Bridging mutational load and immune checkpoints efficacy. Oncoimmunology 3:e27817.
  Chen, Z., Cheng, K., Walton, Z., Wang, Y., Ebi, H., Shimamura, T., Liu, Y., Tupper, T., Ouyang, J., Li, J., Gao, P., Woo, M.S., Xu, C., Yanagita, M., Altabef, A., Wang, S., Lee, C., Nakada, Y., Pena, C.G., Sun, Y., Franchetti, Y., Yao, C., Saur, A., Cameron, M.D., Nishino, M., Hayes, D.N., Wilkerson, M.D., Roberts, P.J., Lee, C.B., Bardeesy, N., Butaney, M., Chirieac, L.R., Costa, D.B., Jackman, D., Sharpless, N.E., Castrillon, D.H., Demetri, G.D., Janne, P.A., Pandolfi, P.P., Cantley, L.C., Kung, A.L., Engelman, J.A., and Wong, K.K. 2012. A murine lung cancer co‐clinical trial identifies genetic modifiers of therapeutic response. Nature 483:613‐617.
  Chin, L., Pomerantz, J., Polsky, D., Jacobson, M., Cohen, C., Cordon‐Cardo, C., Horner, J.W., 2nd, and DePinho, R.A. 1997. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev. 11:2822‐2834.
  Chin, L., Tam, A., Pomerantz, J., Wong, M., Holash, J., Bardeesy, N., Shen, Q., O'Hagan, R., Pantginis, J., Zhou, H., Horner, J.W., 2nd, Cordon‐Cardo, C., Yancopoulos, G.D., and DePinho, R.A. 1999. Essential role for oncogenic Ras in tumour maintenance. Nature 400:468‐472.
  Cox, A.D., Fesik, S.W., Kimmelman, A.C., Luo, J., and Der, C.J. 2014. Drugging the undruggable RAS: Mission possible? Nat. Rev. Drug Discov. 13:828‐851.
  De Raedt, T., Walton, Z., Yecies, J.L., Li, D., Chen, Y., Malone, C.F., Maertens, O., Jeong, S.M., Bronson, R.T., Lebleu, V., Kalluri, R., Normant, E., Haigis, M.C., Manning, B.D., Wong, K.K., Macleod, K.F., and Cichowski, K. 2011. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras‐driven tumors. Cancer Cell 20:400‐413.
  Dovey, J.S., Zacharek, S.J., Kim, C.F., and Lees, J.A. 2008. Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proc. Natl. Acad. Sci. U.S.A. 105:11857‐11862.
  DuPage, M., Dooley, A.L., and Jacks, T. 2009. Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat. Protoc. 4:1064‐1072.
  Engelman, J.A., Chen, L., Tan, X., Crosby, K., Guimaraes, A.R., Upadhyay, R., Maira, M., McNamara, K., Perera, S.A., Song, Y., Chirieac, L.R., Kaur, R., Lightbown, A., Simendinger, J., Li, T., Padera, R.F., Garcia‐Echeverria, C., Weissleder, R., Mahmood, U., Cantley, L.C., and Wong, K.K. 2008. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14:1351‐1356.
  Fisher, G.H., Wellen, S.L., Klimstra, D., Lenczowski, J.M., Tichelaar, J.W., Lizak, M.J., Whitsett, J.A., Koretsky, A., and Varmus, H.E. 2001. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K‐Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 15:3249‐3262.
  Floyd, H.S., Farnsworth, C.L., Kock, N.D., Mizesko, M.C., Little, J.L., Dance, S.T., Everitt, J., Tichelaar, J., Whitsett, J.A., and Miller, M.S. 2005. Conditional expression of the mutant Ki‐rasG12C allele results in formation of benign lung adenomas: development of a novel mouse lung tumor model. Carcinogenesis 26:2196‐2206.
  Fruh, M., De Ruysscher, D., Popat, S., Crino, L., Peters, S., and Felip, E. 2013. Small‐cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow‐up. Ann. Oncol. 24:vi99‐vi105.
  Govindan, R., Ding, L., Griffith, M., Subramanian, J., Dees, N.D., Kanchi, K.L., Maher, C.A., Fulton, R., Fulton, L., Wallis, J., Chen, K., Walker, J., McDonald, S., Bose, R., Ornitz, D., Xiong, D., You, M., Dooling, D.J., Watson, M., Mardis, E.R., and Wilson, R.K. 2012. Genomic landscape of non‐small cell lung cancer in smokers and never‐smokers. Cell 150:1121‐1134.
  Granville, C.A., Memmott, R.M., Balogh, A., Mariotti, J., Kawabata, S., Han, W., Lopiccolo, J., Foley, J., Liewehr, D.J., Steinberg, S.M., Fowler, D.H., Hollander, M.C., and Dennis, P.A. 2009. A central role for Foxp3+ regulatory T cells in K‐Ras‐driven lung tumorigenesis. PloS One 4:e5061.
  Guerra, C., Mijimolle, N., Dhawahir, A., Dubus, P., Barradas, M., Serrano, M., Campuzano, V., and Barbacid, M. 2003. Tumor induction by an endogenous K‐ras oncogene is highly dependent on cellular context. Cancer Cell 4:111‐120.
  Gupta, S., Ramjaun, A.R., Haiko, P., Wang, Y., Warne, P.H., Nicke, B., Nye, E., Stamp, G., Alitalo, K., and Downward, J. 2007. Binding of ras to phosphoinositide 3‐kinase p110alpha is required for ras‐driven tumorigenesis in mice. Cell 129:957‐968.
  Hatley, M.E., Patrick, D.M., Garcia, M.R., Richardson, J.A., Bassel‐Duby, R., van Rooij, E., and Olson, E.N. 2010. Modulation of K‐Ras‐dependent lung tumorigenesis by MicroRNA‐21. Cancer Cell 18:282‐293.
  Hollander, M.C., Maier, C.R., Hobbs, E.A., Ashmore, A.R., Linnoila, R.I., and Dennis, P.A. 2011. Akt1 deletion prevents lung tumorigenesis by mutant K‐ras. Oncogene 30:1812‐1821.
  Imielinski, M., Berger, A.H., Hammerman, P.S., Hernandez, B., Pugh, T.J., Hodis, E., Cho, J., Suh, J., Capelletti, M., Sivachenko, A., Sougnez, C., Auclair, D., Lawrence, M.S., Stojanov, P., Cibulskis, K., Choi, K., de Waal, L., Sharifnia, T., Brooks, A., Greulich, H., Banerji, S., Zander, T., Seidel, D., Leenders, F., Ansen, S., Ludwig, C., Engel‐Riedel, W., Stoelben, E., Wolf, J., Goparju, C., Thompson, K., Winckler, W., Kwiatkowski, D., Johnson, B.E., Janne, P.A., Miller, V.A., Pao, W., Travis, W.D., Pass, H.I., Gabriel, S.B., Lander, E.S., Thomas, R.K., Garraway, L.A., Getz, G., and Meyerson, M. 2012. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150:1107‐1120.
  Iwanaga, K., Yang, Y., Raso, M.G., Ma, L., Hanna, A.E., Thilaganathan, N., Moghaddam, S., Evans, C.M., Li, H., Cai, W.W., Sato, M., Minna, J.D., Wu, H., Creighton, C.J., Demayo, F.J., Wistuba, II, and Kurie, J.M. 2008. Pten inactivation accelerates oncogenic K‐ras‐initiated tumorigenesis in a mouse model of lung cancer. Cancer Res. 68:1119‐1127.
  Jackson, E.L., Olive, K.P., Tuveson, D.A., Bronson, R., Crowley, D., Brown, M., and Jacks, T. 2005. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65:10280‐10288.
  Jackson, E.L., Willis, N., Mercer, K., Bronson, R.T., Crowley, D., Montoya, R., Jacks, T., and Tuveson, D.A. 2001. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K‐ras. Genes Dev. 15:3243‐3248.
  Ji, H., Ramsey, M.R., Hayes, D.N., Fan, C., McNamara, K., Kozlowski, P., Torrice, C., Wu, M.C., Shimamura, T., Perera, S.A., Liang, M.C., Cai, D., Naumov, G.N., Bao, L., Contreras, C.M., Li, D., Chen, L., Krishnamurthy, J., Koivunen, J., Chirieac, L.R., Padera, R.F., Bronson, R.T., Lindeman, N.I., Christiani, D.C., Lin, X., Shapiro, G.I., Janne, P.A., Johnson, B.E., Meyerson, M., Kwiatkowski, D.J., Castrillon, D.H., Bardeesy, N., Sharpless, N.E., and Wong, K.K. 2007. LKB1 modulates lung cancer differentiation and metastasis. Nature 448:807‐810.
  Johnson, L., Mercer, K., Greenbaum, D., Bronson, R.T., Crowley, D., Tuveson, D.A., and Jacks, T. 2001. Somatic activation of the K‐ras oncogene causes early onset lung cancer in mice. Nature 410:1111‐1116.
  Jonkers, J., Meuwissen, R., van der Gulden, H., Peterse, H., van der Valk, M., and Berns, A. 2001. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 29:418‐425.
  Kapoor, A., Yao, W., Ying, H., Hua, S., Liewen, A., Wang, Q., Zhong, Y., Wu, C.J., Sadanandam, A., Hu, B., Chang, Q., Chu, G.C., Al‐Khalil, R., Jiang, S., Xia, H., Fletcher‐Sananikone, E., Lim, C., Horwitz, G.I., Viale, A., Pettazzoni, P., Sanchez, N., Wang, H., Protopopov, A., Zhang, J., Heffernan, T., Johnson, R.L., Chin, L., Wang, Y.A., Draetta, G., and DePinho, R.A. 2014. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158:185‐197.
  Karreth, F.A., Frese, K.K., DeNicola, G.M., Baccarini, M., and Tuveson, D.A. 2011. C‐Raf is required for the initiation of lung cancer by K‐Ras(G12D). Cancer Discov. 1:128‐136.
  Kasinski, A.L., Kelnar, K., Stahlhut, C., Orellana, E., Zhao, J., Shimer, E., Dysart, S., Chen, X., Bader, A.G., and Slack, F.J. 2014. A combinatorial microRNA therapeutics approach to suppressing non‐small cell lung cancer. Oncogene [ePub ahead of print].
  Kogan, S.C., Lagasse, E., Atwater, S., Bae, S.C., Weissman, I., Ito, Y., and Bishop, J.M. 1998. The PEBP2betaMYH11 fusion created by Inv(16)(p13;q22) in myeloid leukemia impairs neutrophil maturation and contributes to granulocytic dysplasia. Proc. Natl. Acad. Sci. U.S.A. 95:11863‐11868.
  Kumar, M.S., Hancock, D.C., Molina‐Arcas, M., Steckel, M., East, P., Diefenbacher, M., Armenteros‐Monterroso, E., Lassailly, F., Matthews, N., Nye, E., Stamp, G., Behrens, A., and Downward, J. 2012. The GATA2 transcriptional network is requisite for RAS oncogene‐driven non‐small cell lung cancer. Cell 149:642‐655.
  Kwon, M.C. and Berns, A. 2013. Mouse models for lung cancer. Mol. Oncol. 7:165‐177.
  Lee, C.L., Moding, E.J., Huang, X., Li, Y., Woodlief, L.Z., Rodrigues, R.C., Ma, Y., and Kirsch, D.G. 2012. Generation of primary tumors with Flp recombinase in FRT‐flanked p53 mice. Dis. Model. Mech. 5:397‐402.
  Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Harada, M., Yoshizawa, H., Kinoshita, I., Fujita, Y., Okinaga, S., Hirano, H., Yoshimori, K., Harada, T., Ogura, T., Ando, M., Miyazawa, H., Tanaka, T., Saijo, Y., Hagiwara, K., Morita, S., and Nukiwa, T. 2010. Gefitinib or chemotherapy for non‐small‐cell lung cancer with mutated EGFR. N. Engl. J. Med. 362:2380‐2388.
  Mainardi, S., Mijimolle, N., Francoz, S., Vicente‐Duenas, C., Sanchez‐Garcia, I., and Barbacid, M. 2014. Identification of cancer initiating cells in K‐Ras driven lung adenocarcinoma. Proc. Natl. Acad. Sci. U.S.A. 111:255‐260.
  Mukhopadhyay, A., Berrett, K.C., Kc, U., Clair, P.M., Pop, S.M., Carr, S.R., Witt, B.L., and Oliver, T.G. 2014. Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer. Cell Rep. 8:40‐49.
  Muzumdar, M.D., Tasic, B., Miyamichi, K., Li, L., and Luo, L. 2007. A global double‐fluorescent Cre reporter mouse. Genesis 45:593‐605.
  Namati, E., Thiesse, J., Sieren, J.C., Ross, A., Hoffman, E.A., and McLennan, G. 2010. Longitudinal assessment of lung cancer progression in the mouse using in vivo micro‐CT imaging. Med. Phys. 37:4793‐4805.
  Okayama, H., Saito, M., Oue, N., Weiss, J.M., Stauffer, J., Takenoshita, S., Wiltrout, R.H., Hussain, S.P., and Harris, C.C. 2013. NOS2 enhances KRAS‐induced lung carcinogenesis, inflammation and microRNA‐21 expression. Int. J. Cancer 132:9‐18.
  Ostrem, J.M., Peters, U., Sos, M.L., Wells, J.A., and Shokat, K.M. 2013. K‐Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548‐551.
  Perez, B.A., Ghafoori, A.P., Lee, C.L., Johnston, S.M., Li, Y., Moroshek, J.G., Ma, Y., Mukherjee, S., Kim, Y., Badea, C.T., and Kirsch, D.G. 2013. Assessing the radiation response of lung cancer with different gene mutations using genetically engineered mice. Front. Oncol. 3:72.
  Puyol, M., Martin, A., Dubus, P., Mulero, F., Pizcueta, P., Khan, G., Guerra, C., Santamaria, D., and Barbacid, M. 2010. A synthetic lethal interaction between K‐Ras oncogenes and Cdk4 unveils a therapeutic strategy for non‐small cell lung carcinoma. Cancer Cell 18:63‐73.
  Reck, M., Popat, S., Reinmuth, N., De Ruysscher, D., Kerr, K.M., and Peters, S. 2014. Metastatic non‐small‐cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow‐up. Ann. Oncol. 25:iii27‐iii39.
  Rhim, A.D., Mirek, E.T., Aiello, N.M., Maitra, A., Bailey, J.M., McAllister, F., Reichert, M., Beatty, G.L., Rustgi, A.K., Vonderheide, R.H., Leach, S.D., and Stanger, B.Z. 2012. EMT and dissemination precede pancreatic tumor formation. Cell 148:349‐361.
  Schönhuber, N., Seidler, B., Schuck, K., Veltkamp, C., Schachtler, C., Zukowska, M., Eser, S., Feyerabend, T.B., Paul, M.C., Eser, P., Klein, S., Lowy, A.M., Banerjee, R., Yang, F., Lee, C.L., Moding, E.J., Kirsch, D.G., Scheideler, A., Alessi, D.R., Varela, I., Bradley, A., Kind, A., Schnieke, A.E., Rodewald, H.R., Rad, R., Schmid, R.M., Schneider, G., and Saur, D. 2014. A next‐generation dual‐recombinase system for time‐ and host‐specific targeting of pancreatic cancer. Nat. Med. 20:1340‐1347.
  Shackelford, D.B., Abt, E., Gerken, L., Vasquez, D.S., Seki, A., Leblanc, M., Wei, L., Fishbein, M.C., Czernin, J., Mischel, P.S., and Shaw, R.J. 2013. LKB1 inactivation dictates therapeutic response of non‐small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23:143‐158.
  Shaw, A.T., Kim, D.W., Nakagawa, K., Seto, T., Crino, L., Ahn, M.J., De Pas, T., Besse, B., Solomon, B.J., Blackhall, F., Wu, Y.L., Thomas, M., O'Byrne, K.J., Moro‐Sibilot, D., Camidge, D.R., Mok, T., Hirsh, V., Riely, G.J., Iyer, S., Tassell, V., Polli, A., Wilner, K.D., and Janne, P.A. 2013. Crizotinib versus chemotherapy in advanced ALK‐positive lung cancer. N. Engl. J. Med. 368:2385‐2394.
  Shepherd F.A., Rodrigues Pereira, J., Ciuleanu, T., Tan, E.H., Hirsh, V., Thongprasert, S., Campos, D., Maoleekoonpiroj, S., Smylie, M., Martins, R., van Kooten, M., Dediu, M., Findlay, B., Tu, D., Johnston, D., Bezjak, A., Clark, G., Santabárbara, P., Seymour, L.; and National Cancer Institute of Canada Clinical Trials Group. 2005. Erlotinib in previously treated non‐small‐cell lung cancer. N. Engl. J. Med. 353:123‐132.
  Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J.M., Desrichard, A., Walsh, L.A., Postow, M.A., Wong, P., Ho, T.S., Hollmann, T.J., Bruggeman, C., Kannan, K., Li, Y., Elipenahli, C., Liu, C., Harbison, C.T., Wang, L., Ribas, A., Wolchok, J.D., and Chan, T.A. 2014. Genetic basis for clinical response to CTLA‐4 blockade in melanoma. N. Engl. J. Med. 371:2189‐2199.
  Sotillo, R., Schvartzman, J.M., Socci, N.D., and Benezra, R. 2010. Mad2‐induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature 464:436‐440.
  Sotillo, R., Hernando, E., Diaz‐Rodriguez, E., Teruya‐Feldstein, J., Cordon‐Cardo, C., Lowe, S.W., and Benezra, R. 2007. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11:9‐23.
  Soucek, L., Whitfield, J.R., Sodir, N.M., Masso‐Valles, D., Serrano, E., Karnezis, A.N., Swigart, L.B., and Evan, G.I. 2013. Inhibition of Myc family proteins eradicates KRas‐driven lung cancer in mice. Genes Dev. 27:504‐513.
  Srinivas, S., Watanabe, T., Lin, C.S., William, C.M., Tanabe, Y., Jessell, T.M., and Costantini, F. 2001. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1:4.
  Sun, Q., Burke, J.P., Phan, J., Burns, M.C., Olejniczak, E.T., Waterson, A.G., Lee, T., Rossanese, O.W., and Fesik, S.W. 2012. Discovery of small molecules that bind to K‐Ras and inhibit Sos‐mediated activation. Angew. Chem. Int. Ed. Engl. 51:6140‐6143.
  TCGA Network. 2014. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543‐550.
  Vansteenkiste, J., De Ruysscher, D., Eberhardt, W.E., Lim, E., Senan, S., Felip, E., and Peters, S. 2013. Early and locally advanced non‐small‐cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow‐up. Ann. Oncol. 24:vi89‐vi98.
  Wang, Y., Zhang, Z., Yan, Y., Lemon, W.J., LaRegina, M., Morrison, C., Lubet, R., and You, M. 2004. A chemically induced model for squamous cell carcinoma of the lung in mice: Histopathology and strain susceptibility. Cancer Res. 64:1647‐1654.
  Weir, B.A., Woo, M.S., Getz, G., Perner, S., Ding, L., Beroukhim, R., Lin, W.M., Province, M.A., Kraja, A., Johnson, L.A., Shah, K., Sato, M., Thomas, R.K., Barletta, J.A., Borecki, I.B., Broderick, S., Chang, A.C., Chiang, D.Y., Chirieac, L.R., Cho, J., Fujii, Y., Gazdar, A.F., Giordano, T., Greulich, H., Hanna, M., Johnson, B.E., Kris, M.G., Lash, A., Lin, L., Lindeman, N., Mardis, E.R., McPherson, J.D., Minna, J.D., Morgan, M.B., Nadel, M., Orringer, M.B., Osborne, J.R., Ozenberger, B., Ramos, A.H., Robinson, J., Roth, J.A., Rusch, V., Sasaki, H., Shepherd, F., Sougnez, C., Spitz, M.R., Tsao, M.S., Twomey, D., Verhaak, R.G., Weinstock, G.M., Wheeler, D.A., Winckler, W., Yoshizawa, A., Yu, S., Zakowski, M.F., Zhang, Q., Beer, D.G., Wistuba, II, Watson, M.A., Garraway, L.A., Ladanyi, M., Travis, W.D., Pao, W., Rubin, M.A., Gabriel, S.B., Gibbs, R.A., Varmus, H.E., Wilson, R.K., Lander, E.S., and Meyerson, M. 2007. Characterizing the cancer genome in lung adenocarcinoma. Nature 450:893‐898.
  Westcott, P.M., Halliwill, K.D., To, M.D., Rashid, M., Rust, A.G., Keane, T.M., Delrosario, R., Jen, K.Y., Gurley, K.E., Kemp, C.J., Fredlund, E., Quigley, D.A., Adams, D.J., and Balmain, A. 2015. The mutational landscapes of genetic and chemical models of Kras‐driven lung cancer. Nature 517:489‐492.
  Xu, C., Fillmore, C.M., Koyama, S., Wu, H., Zhao, Y., Chen, Z., Herter‐Sprie, G.S., Akbay, E.A., Tchaicha, J.H., Altabef, A., Reibel, J.B., Walton, Z., Ji, H., Watanabe, H., Janne, P.A., Castrillon, D.H., Rustgi, A.K., Bass, A.J., Freeman, G.J., Padera, R.F., Dranoff, G., Hammerman, P.S., Kim, C.F., and Wong, K.K. 2014. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD‐L1 expression. Cancer Cell 25:590‐604.
  Xue, W., Meylan, E., Oliver, T.G., Feldser, D.M., Winslow, M.M., Bronson, R., and Jacks, T. 2011. Response and resistance to NF‐kappaB inhibitors in mouse models of lung adenocarcinoma. Cancer Discov. 1:236‐247.
  Yadav, M., Jhunjhunwala, S., Phung, Q.T., Lupardus, P., Tanguay, J., Bumbaca, S., Franci, C., Cheung, T.K., Fritsche, J., Weinschenk, T., Modrusan, Z., Mellman, I., Lill, J.R., and Delamarre, L. 2014. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515:572‐576.
  Yang, Y., Iwanaga, K., Raso, M.G., Wislez, M., Hanna, A.E., Wieder, E.D., Molldrem, J.J., Wistuba, II, Powis, G., Demayo, F.J., Kim, C.F., and Kurie, J.M. 2008. Phosphatidylinositol 3‐kinase mediates bronchioalveolar stem cell expansion in mouse models of oncogenic K‐ras‐induced lung cancer. PloS One 3:e2220.
  Yang, Y., Ahn, Y.H., Gibbons, D.L., Zang, Y., Lin, W., Thilaganathan, N., Alvarez, C.A., Moreira, D.C., Creighton, C.J., Gregory, P.A., Goodall, G.J., and Kurie, J.M. 2011. The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR‐200‐dependent pathway in mice. J. Clin. Invest. 121:1373‐1385.
  Young, N.P., Crowley, D., and Jacks, T. 2011. Uncoupling cancer mutations reveals critical timing of p53 loss in sarcomagenesis. Cancer Res. 71:4040‐4047.
  Zhu, Z., Aref, A.R., Cohoon, T.J., Barbie, T.U., Imamura, Y., Yang, S., Moody, S.E., Shen, R.R., Schinzel, A.C., Thai, T.C., Reibel, J.B., Tamayo, P., Godfrey, J.T., Qian, Z.R., Page, A.N., Maciag, K., Chan, E.M., Silkworth, W., Labowsky, M.T., Rozhansky, L., Mesirov, J.P., Gillanders, W.E., Ogino, S., Hacohen, N., Gaudet, S., Eck, M.J., Engelman, J.A., Corcoran, R.B., Wong, K.K., Hahn, W.C., and Barbie, D.A. 2014. Inhibition of KRAS‐driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov. 4:452‐465.
PDF or HTML at Wiley Online Library