A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response
Open accessAbstract
Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.
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By immunohistochemistry, LKB1 deficiency correlates with no added benefit from bevacizumab plus platinum doublet chemotherapy.
“LKB1 deficiency by immunohistochemistry is associated with lack of benefit from the addition of the vascular endothelial growth factor A (VEGFA) inhibitor bevacizumab to platinum doublet chemotherapy163, 164.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [164]
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Cites
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810699 · Cited by 8,261 · see citing works
Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR
Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Harada, M., Yoshizawa, H., Kinoshita, I., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0909530 · Cited by 5,525 · see citing works
Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors
Demetri, G. D., von Mehren, M., Blanke, C. D., Van den Abbeele, A. D., Eisenberg, B., Roberts, P. J., Heinrich, M. C., Tuveson, D. A., Singer, S., Janicek, M., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa020461 · Cited by 4,389 · see citing works
Self-citationUse of all-trans retinoic acid in the treatment of acute promyelocytic leukemia
Huang, M., Ye, Y., Chen, S. R., Chai, J., Lu, J., Zhoa, L., Gu, L.-J., & Wang, Z.-Y. (1988) · Blood · doi:10.1182/blood.v72.2.567.567 · Cited by 2,445 · see citing works
Nagata, Y., Lan, K.-H., Zhou, X., Tan, M., Esteva, F. J., Sahin, A. A., Klos, K. S., Li, P., Monia, B. P., Nguyen, N. T., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.022 · Cited by 1,858 · see citing works
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
Self-citationCharacterizing the cancer genome in lung adenocarcinoma
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., et al. (2007) · Nature · doi:10.1038/nature06358 · Cited by 1,105 · see citing works
Self-citationLKB1 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-citationMascaux, C., Iannino, N., Martin, B., Paesmans, M., Berghmans, T., Dusart, M., Haller, A., Lothaire, P., Meert, A.-P., Noël, S., et al. (2004) · British Journal of Cancer · doi:10.1038/sj.bjc.6602258 · Cited by 604 · see citing works
Yeh, T. C., Marsh, V., Bernat, B. A., Ballard, J., Colwell, H., Evans, R. J., Parry, J., Smith, D. J., Brandhuber, B. J., Gross, S. D., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1150 · Cited by 583 · see citing works
Berghmans, T., Dusart, M., Paesmans, M., Hossein-Foucher, C., Buvat, I., Castaigne, C., Scherpereel, A., Mascaux, C., Moreau, M., Roelandts, M., et al. (2008) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e31815e6d6b · Cited by 524 · see citing works
Douillard, J.-Y., Shepherd, F. A., Hirsh, V., Mok, T., Socinski, M. A., Gervais, R., Liao, M.-L., Bischoff, H., Reck, M., Sellers, M. V., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.24.3030 · Cited by 492 · see citing works
Vansteenkiste, J., Stroobants, S. G., Dupont, P. J., Leyn, P. R. D., Verbeken, E. K., Deneffe, G. J., Mortelmans, L. A., & Demedts, M. (1999) · Journal of Clinical Oncology · doi:10.1200/jco.1999.17.10.3201 · Cited by 438 · see citing works
Steels, E., Paesmans, M., Berghmans, T., Branle, F., Lemaitre, F., Mascaux, C., Meert, A., Vallot, F., Lafitte, J., & Sculier, J. (2001) · European Respiratory Journal · doi:10.1183/09031936.01.00062201 · Cited by 418 · see citing works
Prevalence and specificity of LKB1 genetic alterations in lung cancers
Matsumoto, S., Iwakawa, R., Takahashi, K., Kohno, T., Nakanishi, Y., Matsuno, Y., Suzuki, K., Nakamoto, M., Shimizu, E., Minna, J. D., et al. (2007) · Oncogene · doi:10.1038/sj.onc.1210418 · Cited by 280 · see citing works
Carretero, J., Shimamura, T., Rikova, K., Jackson, A. L., Wilkerson, M. D., Borgman, C. L., Buttarazzi, M., Sanofsky, B. A., McNamara, K. L., Brandstetter, K. A., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.04.026 · Cited by 243 · see citing works
Self-citationLi, D., Shimamura, T., Ji, H., Chen, L., Haringsma, H. J., McNamara, K. L., Liang, M., Perera, S. A., Zaghlul, S., Borgman, C. L., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.06.005 · Cited by 242 · see citing works
Self-citationp53 Mutations and Survival in Stage I Non-Small-Cell Lung Cancer: Results of a Prospective Study
Ahrendt, S. A., Hu, Y. C., Buta, M. R., McDermott, M., Benoit, N. E., Yang, S. C., Wu, L., & Sidransky, D. (2003) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/95.13.961 · Cited by 222 · see citing works
Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models
Singh, M., Lima, A., Molina, R., Hamilton, P., Clermont, A. C., Devasthali, V., Thompson, J. D., Cheng, J. H., Reslan, H. B., Ho, C., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1640 · Cited by 215 · see citing works
Self-citationJi, H., Wang, Z., Perera, S. A., Li, D., Liang, M., Zaghlul, S., McNamara, K. L., Chen, L., Albert, M., Sun, Y., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4592 · Cited by 174 · see citing works
Self-citationHainsworth, J. D., Cebotaru, C. L., Kanarev, V., Ciuleanu, T., Damyanov, D., Stella, P. J., Ganchev, H., Pover, G. M., Morris, C. D., & Tzekova, V. (2010) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3181e8b3a3 · Cited by 162 · see citing works
Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer
Gill, R. K., Yang, S.-H., Meerzaman, D. M., Mechanic, L. E., Bowman, E. D., Jeon, H.-S., Roy‐Chowdhuri, S., Shakoori, A., Dracheva, T., Hong, K.-M., et al. (2011) · Oncogene · doi:10.1038/onc.2011.98 · Cited by 127 · see citing works
How Genetically Engineered Mouse Tumor Models Provide Insights Into Human Cancers
Politi, K. A., & Pao, W. J. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.30.8304 · Cited by 122 · see citing works
Zhao, B., Oxnard, G. R., Moskowitz, C. S., Kris, M. G., Pao, W. J., Guo, P., Rusch, V. W., Ladanyi, M., Rizvi, N. A., & Schwartz, L. H. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-0125 · Cited by 111 · see citing works
Cancer lessons from mice to humans
Tuveson, D. A., & Hanahan, D. (2011) · Nature · doi:10.1038/471316a · Cited by 86 · see citing works
CT Tumor Volume Measurement in Advanced Non-small-cell Lung Cancer
Nishino, M., Guo, M., Jackman, D. M., DiPiro, P. J., Yap, J. T., Ho, T. T. N., Hatabu, H., Janne, P. A., den Abbeele, A. D. V., & Johnson, B. E. (2010) · Academic Radiology · doi:10.1016/j.acra.2010.08.021 · Cited by 82 · see citing works
Self-citationPhase I and Pharmacokinetic Study of Lapatinib and Docetaxel in Patients With Advanced Cancer
LoRusso, P. M., Jones, S. F., Koch, K. M., Arya, N., Fleming, R. A., Loftiss, J., Pandite, L. N., Gadgeel, S. M., Weber, B. L., & Burris, H. A. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.9633 · Cited by 68 · see citing works
Pulse-oximetry accurately predicts lung pathology and the immune response during influenza infection
Verhoeven, D. E., Teijaro, J. R., & Färber, D. L. (2009) · Virology · doi:10.1016/j.virol.2009.05.004 · Cited by 65 · see citing works
Response of human tumor xenografts in athymic nude mice to docetaxel (RP 56976, Taxotere®)
Dykes, D. J., Bissery, M. C., Harrison, S. D., & Waud, W. R. (1995) · Investigational New Drugs · doi:10.1007/bf02614214 · Cited by 45 · see citing works
Prognosis and Reevaluation of Lung Cancer by Positron Emission Tomography Imaging
Erasmus, J. J., ROHREN, E. M., & Swisher, S. G. (2009) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200806-059lc · Cited by 31 · see citing works
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Metabolic reprogramming and cancer progression
Faubert, B., Solmonson, A., & DeBerardinis, R. J. (2020) · Science · doi:10.1126/science.aaw5473 · Cited by 2,740 · see citing works
Non-small-cell lung cancers: a heterogeneous set of diseases
Chen, Z., Brainson, C. F., Hammerman, P. S., Kim, C. F., & Wong, K. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3775 · Cited by 1,935 · see citing works
Self-citationPatient-Derived Xenograft Models: An Emerging Platform for Translational Cancer Research
Hidalgo, M. M., Amant, F. C., Biankin, A. V., Budínská, E., Byrne, A. T., Caldas, C., Clarke, R. B., de Jong, S., Jonkers, J., Mælandsmo, G. M., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0001 · Cited by 1,759 · see citing works
“In their original format, these studies refer to the use of GEMMs of cancer to determine patient selection strategies as well as to discover mechanisms of resistance to treatment approaches (51, 52).”
BackgroundDrug delivery systems for RNA therapeutics
Paunovska, K., Loughrey, D., & Dahlman, J. E. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-021-00439-4 · Cited by 1,349 · see citing works
Organs-on-chips at the frontiers of drug discovery
Esch, E. W., Bahinski, A., & Huh, D. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4539 · Cited by 1,185 · see citing works
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
Skoulidis, F., Byers, L. A., Diao, L., Papadimitrakopoulou, V. A., Tong, P., Izzo, J., Behrens, C., Kadara, H., Parra, E. R., Canales, J. R., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-1236 · Cited by 936 · see citing works
“Preclinical studies have indicated that Kras-mutant lung tumors bearing Trp53 or Stk11/Lkb1 co-mutations differ in their response to docetaxel with or without selumetinib, suggesting that co-mutations may also affect treatment responsiveness (11).”
Self-citationHow cancer metabolism is tuned for proliferation and vulnerable to disruption
Schulze, A., & Harris, A. L. (2012) · Nature · doi:10.1038/nature11706 · Cited by 927 · see citing works
Basu, A. B., Bodycombe, N. E., Cheah, J. H., Price, E. V., Liu, K., Schaefer, G. I., Ebright, R. Y., Stewart, M. L., Ito, D., Wang, S. Y., et al. (2013) · Cell · doi:10.1016/j.cell.2013.08.003 · Cited by 820 · see citing works
“The top-ranked gene, STK11, has been implicated in resistance to docetaxel in a murine model of KRAS mutant lung cancer (Chen et al., 2012).”
BackgroundSelf-citationCDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation
Deng, J., Wang, E. S., Jenkins, R. W., Li, S., Dries, R., Yates, K., Chhabra, S., Huang, W., Liu, H., Aref, A. R., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0915 · Cited by 770 · see citing works
“The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”
BackgroundMethodInfluentialSelf-citationPatnaik, A., Rosen, L. S., Tolaney, S. M., Tolcher, A. W., Goldman, J. W., Gandhi, L., Papadopoulos, K. P., Beeram, M., Rasco, D. W., Hilton, J. F., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0095 · Cited by 743 · see citing works
Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges
Day, C.-P., Merlino, G., & Van Dyke, T. (2015) · Cell · doi:10.1016/j.cell.2015.08.068 · Cited by 676 · see citing works
Jänne, P. A., Shaw, A. T., Pereira, J. R., Jeannin, G., Vansteenkiste, J., Barrios, C., Franke, F. A., Grinsted, L., Zazulina, V., Smith, P., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70489-8 · Cited by 655 · see citing works
Koyama, S., Akbay, E. A., Li, Y. Y., Aref, A. R., Skoulidis, F., Herter-Sprie, G. S., Buczkowski, K. A., Liu, Y., Awad, M. M., Denning, W. L., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-1439 · Cited by 640 · see citing works
“Lkb1-deficient Kras-mutated (Kras/Lkb1) tumors show a more invasive and metastatic phenotype with significantly reduced survival (3), and differential drug sensitivities as compared with Kras-mutant Lkb1-wild-type tumors and Kras-mutated compound Tp53-deficient animals (4).”
Self-citationMEK1 and MEK2 inhibitors and cancer therapy: the long and winding road
Caunt, C. J., Sale, M. J., Smith, P. D., & Cook, S. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc4000 · Cited by 606 · see citing works
Animal models of human disease: challenges in enabling translation
McGonigle, P., & Ruggeri, B. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.08.006 · Cited by 610 · see citing works
Shackelford, D. B., Abt, E., Gerken, L., Vasquez, D. S., Seki, A., Leblanc, M., Wei, L., Fishbein, M. C., Czernin, J., Mischel, P. S., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2012.12.008 · Cited by 585 · see citing works
“Studies in genetically engineered mouse models have shown that simultaneous activation of Kras and biallelic deletion of Lkb1 in the lung dramatically increases tumor burden andmetastasis (Carretero et al., 2010; Chen et al., 2012; Ji et al., 2007).”
InfluentialGenetically engineered mouse models in oncology research and cancer medicine
Kersten, K., de Visser, K. E., van Miltenburg, M. H., & Jonkers, J. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201606857 · Cited by 502 · see citing works
“…that Kras / Lkb1 -mutant lung tumors are more resistant to combination therapy with docetaxel and the MEK inhibitor selumetinib than Kras - or Kras / p53 -mutant tumors, highlighting LKB1 as a potential determinant of resistance in clinical trials with this combination therapy (Chen et al , 2012).”
Strategies for optimizing the response of cancer and normal tissues to radiation
Moding, E. J., Kastan, M. B., & Kirsch, D. G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4003 · Cited by 461 · see citing works
Applications of the CRISPR-Cas9 system in cancer biology
Sánchez-Rivera, F. J., & Jacks, T. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3950 · Cited by 405 · see citing works
Corcoran, R. B., Cheng, K. A., Hata, A. N., Faber, A. C., Ebi, H., Coffee, E. M., Greninger, P., Brown, R. D., Godfrey, J. T., Cohoon, T. J., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2012.11.007 · Cited by 377 · see citing works
Self-citationLKB1 loss links serine metabolism to DNA methylation and tumorigenesis
Kottakis, F., Nicolay, B. N., Roumane, A., Karnik, R., Gu, H., Nagle, J. M., Boukhali, M., Hayward, M. C., Li, Y. Y., Chen, T., et al. (2016) · Nature · doi:10.1038/nature20132 · Cited by 348 · see citing works
Self-citationRuggeri, B., Camp, F., & Miknyoczki, S. J. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.06.020 · Cited by 369 · see citing works
“Given the predictive potential for clinical responsiveness, primary tumorgrafts have effectively become avatar models of human cancer in which to conduct synchronous ‘co-clinical trials’ of novel therapeutic agents similar to studies conducted presently with specific GEMMs [27,28].”
BackgroundMethodZheng, H., Zhao, W., Yan, C., Watson, C. C., Massengill, M. T., Xie, M., Massengill, C., Noyes, D. R., Martinez, G. V., Afzal, R., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2584 · Cited by 339 · see citing works
“The impact of therapeutic regimens identified here on treatment response of KRAS/ STK11 as well as the widely used KRAS/TP53 autochthonous model (38) will therefore also be important to determine.”
BackgroundSelf-citationJänne, P. A., van den Heuvel, M. M., Barlesi, F., Cobo, M., Mazieres, J., Crinò, L., Orlov, S., Blackhall, F., Wolf, J., Garrido, P., et al. (2017) · JAMA · doi:10.1001/jama.2017.3438 · Cited by 335 · see citing works
Chandler, R. L., Damrauer, J. S., Raab, J. R., Schisler, J. C., Wilkerson, M. D., Didion, J. P., Starmer, J., Serber, D., Yee, D., Xiong, J., et al. (2015) · Nature Communications · doi:10.1038/ncomms7118 · Cited by 320 · see citing works
Self-citationA Plasmonic Gold Nanostar Theranostic Probe for In Vivo Tumor Imaging and Photothermal Therapy
Liu, Y., Ashton, J. R., Moding, E. J., Yuan, H., Register, J. K., Fales, A. M., Choi, J., Whitley, M. J., Zhao, X., Qi, Y. P., et al. (2015) · Theranostics · doi:10.7150/thno.11974 · Cited by 311 · see citing works
“Mice with primary sarcomas are immunocompetent and may more accurately reflect the tumor microenvironment and response to therapy of human tumors compared to xenograft models.[44-46] The longitudinal dual-energy CT imaging showed gold nanoparticle distribution at various time points (Figure 3).”
BackgroundSelf-citationKRAS-Mutant non-small cell lung cancer: From biology to therapy
Ferrer, I., Zugazagoitia, J., Herbertz, S., John, W. J., Paz-Ares, L. G., & Schmid‐Bindert, G. (2018) · Lung Cancer · doi:10.1016/j.lungcan.2018.07.013 · Cited by 306 · see citing works
Genetics and biomarkers in personalisation of lung cancer treatment
Rosell, R., Bivona, T. G., & Karachaliou, N. (2013) · The Lancet · doi:10.1016/s0140-6736(13)61715-8 · Cited by 304 · see citing works
Molecularly targeted cancer therapy: some lessons from the past decade
Huang, M., Shen, A., Ding, J., & Geng, M. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.11.004 · Cited by 289 · see citing works
One mouse, one patient paradigm: New avatars of personalized cancer therapy
Malaney, P., Nicosia, S. V., & Davé, V. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.10.010 · Cited by 290 · see citing works
“Concordance between the engrafted murine tumors and the original patient tumors have been established in several cancer models such as non-small cell lung cancer (NSCLC), small cell lung cancer and pancreatic tumors amongst others [11–13].”
BackgroundMethodInfluentialBasket Trials and the Evolution of Clinical Trial Design in an Era of Genomic Medicine
Redig, A. J., & Janne, P. A. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.8433 · Cited by 281 · see citing works
Yu, H. A., Suzawa, K., Jordan, E., Zehir, A., Ni, A., Kim, R., Kris, M. G., Hellmann, M. D., Li, B. T., Somwar, R., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2961 · Cited by 259 · see citing works
“For example, within KRAS-mutant lung cancers, concurrent LKB1 (STK11) andTP53mutationsmaybe associatedwith shorter survival (6–9) and the presence of the former may also confer a greater sensitivity tomTOR orMEK inhibition (10, 11).”
BackgroundYang, H. J., Chu, Q., Li, Y., Tao, L., Zhou, J., Yu, C. Y., Xu, F., Chen, Z., Zhu, F., & Chen, Y. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1230 · Cited by 270 · see citing works
“The knowledge of these agents, their efficacy targets and the targeted pathways is useful not only for the discovery and development of targeted therapeutics (4,5), but also for facilitating the research and development of systems pharmacology (6,7) aimed at the discovery of multitarget drugs (8) and drug combinations…”
BackgroundSelf-citationSmoking, 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
“A recently published coclinical trial in lung cancer described the results of treating mouse models containing single or combined alleles (mutantKras, mutantKrasþTP53 null, or mutant KrasþLKB1 null) with docetaxel alone or docetaxel combined with the MAP–ERK kinase inhibitor selumetinib (AZD6244), a combination being…”
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Xue, W., Dahlman, J. E., Tammela, T., Khan, O. F., Sood, S., Dave, A., Cai, W., Chirino, L. M., Yang, G. R., Bronson, R. T., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1412686111 · Cited by 243 · see citing works
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Grant, T. J., Hua, K., & Singh, A. (2016) · Progress in Molecular Biology and Translational Science · doi:10.1016/bs.pmbts.2016.09.008 · Cited by 237 · see citing works
Targeting tumour-supportive cellular machineries in anticancer drug development
Dobbelstein, M., & Moll, U. M. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4201 · Cited by 229 · see citing works
KRAS Mutation: Should We Test for It, and Does It Matter?
Roberts, P. J., & Stinchcombe, T. E. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.43.0454 · Cited by 228 · see citing works
Self-citationRichardson, A. M., Havel, L. S., Koyen, A. E., Konen, J. M., Shupe, J. A., Wiles, W. G., Martin, W. D., Grossniklaus, H. E., Sica, G., Gilbert‐Ross, M., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1776 · Cited by 228 · see citing works
“As the driving genomic aberrations of lung adenocarcinoma have become clearer, co-mutations in KRAS and LKB1 are recognized as major drivers of the disease (13, 14).”
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Liu, Q., Xu, C., Kirubakaran, S., Zhang, X., Hur, W., Liu, Y., Kwiatkowski, N. P., Wang, J., Westover, K. D., Gao, P., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-1702 · Cited by 212 · see citing works
“The operation of FDG-PET and quantification of SUVmax were described previously(37).”
MethodSelf-citationNaidoo, J., Sima, C. S., Rodriguez, K., Busby, N., Nafa, K., Ladanyi, M., Riely, G. J., Kris, M. G., Arcila, M. E., & Yu, H. A. (2015) · Cancer · doi:10.1002/cncr.29493 · Cited by 211 · see citing works
“In KRAS-mutant tumors, the presence of a concurrent liver kinase B1 (serine/ threonine kinase 11) mutation portends a poor prognosis, and may confer resistance to targeted therapies such as mammalian target of rapamycin (mTOR) and mitogenactivated protein kinase (MEK) kinase inhibition.(31-37) Two of our 3 patients wi…”
BackgroundIs animal research sufficiently evidence based to be a cornerstone of biomedical research?
Pound, P., & Bracken, M. B. (2014) · BMJ · doi:10.1136/bmj.g3387 · Cited by 207 · see citing works
Zhang, M., Yang, W. Z., Wang, P., Deng, Y., Dong, Y., Liu, F., Huang, R., Zhang, P., Duan, Y., Liu, X., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19973-6 · Cited by 212 · see citing works
Li, F., Huang, Q., Luster, T. A., Hu, H., Zhang, H., Ng, W., Khodadadi‐Jamayran, A., Wang, W., Chen, T., Deng, J., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0780 · Cited by 201 · see citing works
“Tumor volume within the whole lung was quantified using 3-D slicer software to reconstruct MRI volumetric measurements, as described previously (58).”
MethodSelf-citationDevelopment 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
Efficacy of BET Bromodomain Inhibition in Kras-Mutant Non–Small Cell Lung Cancer
Shimamura, T., Chen, Z., Soucheray, M., Carretero, J., Kikuchi, E., Tchaicha, J. H., Gao, Y., Cheng, K. A., Cohoon, T. J., Qi, J., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3904 · Cited by 203 · see citing works
“MRI measurements were performed as previously described (20), todetermine the reduction in tumor volume after the indicated time of treatment.”
BackgroundMethodInfluentialSelf-citationDowney, C. M., Aghaei, M., Schwendener, R. A., & Jirik, F. R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0099988 · Cited by 194 · see citing works
“In addition, our study highlights the growing awareness of the utility of GEMMs for preclinical drug studies [28,29].”
BackgroundcAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth
Chen, Z., Li, J., Lin, S., Cao, C., Gimbrone, N. T., Yang, R., Fu, D., Carper, M. B., Haura, E. B., Schabath, M. B., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85250 · Cited by 192 · see citing works
“On the other hand, LKB1 loss impaired the responses of KRAS mutant NSCLC to docetaxel monotherapy; the combination therapy of docetaxel and the MEK inhibitor selumetinib; or dual inhibition of the PI3K and MEK pathways (16, 17).”
BackgroundSelf-citationInhibition of KRAS -Driven Tumorigenicity by Interruption of an Autocrine Cytokine Circuit
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., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0646 · Cited by 193 · see citing works
Self-citationVanderLaan, P. A., Rangachari, D., Mockus, S. M., Spotlow, V., Reddi, H. V., Malcolm, J., Huberman, M. S., Joseph, L. J., Kobayashi, S. S., & Costa, D. B. (2017) · Lung Cancer · doi:10.1016/j.lungcan.2017.01.011 · Cited by 188 · see citing works
“The complete loss of TP53 function can accelerate the transforming potential of driver oncogenes in lung cancers [14] and hamper tumor response to cytotoxic chemotherapy [14], radiotherapy, and/or EGFR inhibitors [15].”
BackgroundSelf-citationAmbrogio, C., Goméz-López, G., Falcone, M., Vidal, A., Nadal, E., Crosetto, N., Blasco, R. B., Fernández-Marcos, P. J., Sánchez‐Céspedes, M., Ren, X., et al. (2016) · Nature Medicine · doi:10.1038/nm.4041 · Cited by 175 · see citing works
Li, F., Han, X., Li, F., Wang, R., Wang, H., Gao, Y., Wang, X., Fang, Z., Zhang, W., Yao, S., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.04.001 · Cited by 169 · see citing works
“The plasticity represents bolic adaptation and drug resistance and holds important the co-clinical trials on genetically engineered mouse models (GEMMs), Lkb1-deficient lung tumors show primary resistance to treatments that are effective to Kras mutant (Kras) or Kras;Trp53 (KP) mutant lung tumors (Chen et al., 2012; S…”
Self-citationChoi, E.-Y. K., Hendley, A. M., Bailey, J. M., Leach, S. D., & Goldenring, J. R. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.11.049 · Cited by 168 · see citing works
The AMPK-Related Kinases SIK1 and SIK3 Mediate Key Tumor-Suppressive Effects of LKB1 in NSCLC
Hollstein, P. E., Eichner, L. J., Brun, S. N., Kamireddy, A., Svensson, R. U., Vera, L. I., Ross, D. S., Rymoff, T. J., Hutchins, A., Galvez, H. M., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1261 · Cited by 168 · see citing works
“mutations, prompting intense study of genetically engineered mouse models of LKB1 loss coupled with Kras activation to understand how deregulation of these two genes drives tumor formation and growth, and response to therapy in lung cancer [4-9].”
BackgroundEx Vivo Tumor Culture Systems for Functional Drug Testing and Therapy Response Prediction
Meijer, T. G., Naipal, K. A. T., Jager, A., & van Gent, D. C. (2017) · Future Science OA · doi:10.4155/fsoa-2017-0003 · Cited by 163 · see citing works
Kitai, H., Ebi, H., Tomida, S., Floros, K. V., Kotani, H., Adachi, Y., Oizumi, S., Nishimura, M., Faber, A. C., & Yano, S. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1377 · Cited by 162 · see citing works
“In line with this, concurrent loss of LKB1 is a cause of resistance to the combination of selumetinib with docetaxel or PI3 kinase inhibitor in KRAS mutant lung tumor model, likely through activated AKT and/or SRC pathways (47,48).”
BackgroundSelf-citationSynergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer
Herter-Sprie, G. S., Koyama, S., Korideck, H., Hai, J., Deng, J., Li, Y. Y., Buczkowski, K. A., Grant, A. K., Ullas, S., Rhee, K., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.87415 · Cited by 161 · see citing works
Self-citationSivakumar, S., Moore, J. A., Montesion, M., Sharaf, R. R., Lin, D. I., Colón, C. I., Fleischmann, Z., Ebot, E. M., Newberg, J. Y., Mills, J. M., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0620 · Cited by 151 · see citing works
Kwon, M.-C., & Berns, A. J. M. (2013) · Molecular Oncology · doi:10.1016/j.molonc.2013.02.010 · Cited by 145 · see citing works
“Likely restricted growth is mediated by cell cycle arrest and cellular senescence imposed by cell-autonomous or microenvironmental cues (Collado et al., 2005).”
BackgroundMirković, J., Sholl, L. M., Garcia, E., Lindeman, N. I., MacConaill, L. E., Hirsch, M. S., Cin, P. D., Gorman, M., Barletta, J. A., Nucci, M. R., et al. (2015) · Modern Pathology · doi:10.1038/modpathol.2015.103 · Cited by 147 · see citing works
Lunardi, A., Ala, U., Epping, M. T., Salmena, L., Clohessy, J. G., Webster, K. A., Wang, G., Roberta Mazzucchelli, A., Bianconi, M., Stack, E. C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2650 · Cited by 144 · see citing works
Self-citationKRAS-G12C Mutation Is Associated with Poor Outcome in Surgically Resected Lung Adenocarcinoma
Nadal, E., Chen, G., Prensner, J. R., Shiratsuchi, H., Sam, C., Zhao, L., Kalemkerian, G. P., Brenner, D. E., Lin, J., Reddy, R. M., et al. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000305 · Cited by 139 · see citing works
Prognostic Impact of KRAS Mutation Subtypes in 677 Patients with Metastatic Lung Adenocarcinomas
Yu, H. A., Sima, C. S., Shen, R., Kass, S. L., Gainor, J. F., Shaw, A. T., Hames, M. L., Iams, W. T., Aston, J. L., Lovly, C. M., et al. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000432 · Cited by 137 · see citing works
mTORC2 in the center of cancer metabolic reprogramming
Masui, K., Cavenee, W. K., & Mischel, P. S. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.04.002 · Cited by 132 · see citing works
Early phase clinical trials to identify optimal dosing and safety
Cook, N., Hansen, A. R., Siu, L. L., & Razak, A. R. A. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.07.025 · Cited by 136 · see citing works
Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future
Uras, I. Z., Moll, H. P., & Casanova, E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124325 · Cited by 134 · see citing works
“Abbreviations A-RAF V-Raf murine sarcoma 3611 viral oncogene homolog 1 AKT Protein kinase B ALK Anaplastic lymphoma receptor tyrosine kinase AMPK AMP-activated protein kinase APC/C Anaphase-promoting complex/cyclosome ASK1 Apoptosis signal-regulating kinase 1 ASO Antisense-oligonucleotide B-RAF V-Raf murine sarcoma vi…”
BackgroundKRAS Mutations as Prognostic and Predictive Markers in Non–Small Cell Lung Cancer
Martin, P., Leighl, N. B., Tsao, M., & Shepherd, F. A. (2013) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318283d958 · Cited by 134 · see citing works
Mouse hospital and co-clinical trial project—from bench to bedside
Clohessy, J. G., & Pandolfi, P. P. (2015) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.62 · Cited by 127 · see citing works
Self-citationLe, X., Negrao, M. V., Reuben, A., Federico, L., Diao, L., McGrail, D. J., Nilsson, M. B., Robichaux, J. P., Guijarro, I., Patel, S. A., et al. (2020) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2020.12.010 · Cited by 126 · see citing works
Self-citationWu, X., Wu, Y., Ye, H., Yu, S., He, C., & Chen, X. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.04.011 · Cited by 125 · see citing works
Hensing, T. A., Chawla, A., Batra, R., & Salgia, R. (2013) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-8778-4_5 · Cited by 125 · see citing works
Therapeutic target database update 2014: a resource for targeted therapeutics
Chu, Q., Zhang, C., Zhu, F., Xu, F., Chen, S. Y., Zhang, P., Li, Y., Yang, S. Y., Wei, Y., Tao, L., et al. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1129 · Cited by 121 · see citing works
“The knowledge of the efficacy targets and biomarkers is useful not only for the discovery and development of targeted therapeutics (11,12) but also for facilitating the development and practice of stratified and personalized medicines (4,13,14).”
BackgroundBristow, R. G., Alexander, B. M., Baumann, M. A., Bratman, S. V., Brown, J. M., Camphausen, K. A., Choyke, P. L., Citrin, D. E., Contessa, J. N., Dicker, A. P., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30096-2 · Cited by 121 · see citing works
Calles, A., Sholl, L. M., Rodig, S. J., Pelton, A. K., Hornick, J. L., Butaney, M., Lydon, C., Dahlberg, S. E., Oxnard, G. R., Jackman, D. M., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-3112 · Cited by 115 · see citing works
“However, in Kras G12D/Lkb1 / GEMMS, selumetinib/docetaxel was significantly less effective (19).”
BackgroundResultInfluentialSelf-citationRHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas
Konstantinidou, G., Ramadori, G., Torti, F., Kangasniemi, K., Ramirez, R. E., Cai, Y., Behrens, C., Dellinger, M. T., Brekken, R. A., Wistuba, I. I., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0388 · Cited by 114 · see citing works
Pettersen, E. O., Ebbesen, P., Gieling, R. G., Williams, K. J., Dubois, L. J., Lambin, P., Ward, C., Meehan, J., Kunkler, I. H., Langdon, S. P., et al. (2014) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.3109/14756366.2014.966704 · Cited by 112 · see citing works
Zhang, Y.-X., Sicinska, E., Czaplinski, J. T., Remillard, S. P., Moss, S., Wang, Y., Brain, C., Loo, A., Snyder, E. L., Demetri, G. D., et al. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0387 · Cited by 114 · see citing works
“Before randomization (T0) and after 3 days of therapy (T3), mice were evaluated by 2-[18F]fluoro-2-deoxy-D-glucose (FDG)-PET imaging (26).”
MethodSelf-citationWu, X., He, C., Wu, Y., Chen, X., & Cheng, J. (2015) · Advanced Functional Materials · doi:10.1002/adfm.201502742 · Cited by 113 · see citing works
Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma
Çeliktaş, M., Tanaka, I., Tripathi, S. C., Fahrmann, J. F., Aguilar-Bonavides, C., Villalobos, P. A., Delgado, O., Dhillon, D. S., Dennison, J. B., Ostrin, E. J., et al. (2016) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djw231 · Cited by 110 · see citing works
Facchinetti, F., Bluthgen, M. V., Tergemina-Clain, G., Faivre, L., Pignon, J., Planchard, D., Remón, J., Soria, J., Lacroix, L., & Besse, B. (2017) · Lung Cancer · doi:10.1016/j.lungcan.2017.08.002 · Cited by 110 · see citing works
Targeting HER2 Aberrations in Non–Small Cell Lung Cancer with Osimertinib
Liu, S., Li, S., Hai, J., Wang, X., Chen, T., Quinn, M. M., Gao, P., Zhang, Y., Ji, H., Cross, D. A. E., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1875 · Cited by 112 · see citing works
“Treatment study HW, DH, and SH26 mice were fed with doxy diets, and lung tumors were monitored by MRI (34).”
MethodInfluentialSelf-citationCombined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
Tang, K. H., Li, S., Khodadadi-Jamayran, A., Jen, J., Han, H., Guidry, K., Chen, T., Hao, Y., Fedele, C., Zebala, J. A., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0369 · Cited by 105 · see citing works
Self-citationModeling and predicting clinical efficacy for drugs targeting the tumor milieu
Singh, M., & Ferrara, N. (2012) · Nature Biotechnology · doi:10.1038/nbt.2286 · Cited by 105 · see citing works
A RAS Renaissance: Emerging Targeted Therapies for KRAS-Mutated Non–Small Cell Lung Cancer
Vasan, N., Boyer, J. L., & Herbst, R. S. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1762 · Cited by 102 · see citing works
“This effect was recapitulated in mouse embryonic fibroblasts and in a KRas-driven GEMM.”
InfluentialAdeegbe, D. O., Liu, S., Hattersley, M. M., Bowden, M., Zhou, C. W., Li, S., Vlahos, R., Grondine, M. R., Dolgalev, I., Ivanova, E. V., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0077 · Cited by 102 · see citing works
“Furthermore,KRASmutation concurrentwithother genetic alterations provokes differential responses to current therapeutics and therapeutic resistance (4, 5).”
BackgroundMethodInfluentialSelf-citationTargeting BET bromodomain proteins in solid tumors
Sahai, V., Redig, A. J., Collier, K. A., Eckerdt, F., & Munshi, H. G. (2016) · Oncotarget · doi:10.18632/oncotarget.9804 · Cited by 103 · see citing works
“A murine co-clinical trial demonstrated that concurrent mutations in LKB1 or TP53 may help mediate differential response to concurrent chemotherapy and MEK inhibition in these tumors, [49] and interestingly, co-expression of mutant LKB1 also limits the effectiveness of JQ1 in KRAS models [50].”
BackgroundCorso, S., Isella, C., Bellomo, S. E., Apicella, M., Durando, S., Migliore, C., Ughetto, S., D’Errico, L., Menegon, S., Moya-Rull, D., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-1166 · Cited by 100 · see citing works
Targeting LKB1 in Cancer – Exposing and Exploiting Vulnerabilities
Momcilovic, M., & Shackelford, D. B. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.261 · Cited by 97 · see citing works
Breakthrough in targeted therapy for non-small cell lung cancer
Zhencong, Y., Huang, Y., Ke, J., Zhu, X. M., Leng, S., & Luo, H. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.111079 · Cited by 95 · see citing works
Development of an ObLiGaRe Doxycycline Inducible Cas9 system for pre-clinical cancer drug discovery
Lundin, A., Porritt, M. J., Jaiswal, H., Seeliger, F., Johansson, C., Bidar, A. W., Badertscher, L., Wimberger, S., Davies, E. J., Hardaker, E. L., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18548-9 · Cited by 100 · see citing works
Lessons Learned from Two Decades of Anticancer Drugs
Liu, Z., Delavan, B., Roberts, R. A., & Tong, W. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.06.005 · Cited by 95 · see citing works
“One promising example of the application of the GEM model for anticancer development is selumetinib (clinical Phase I/II/III), which is designed for the treatment of multiple cancer types, including triple-negative breast cancer [84], nonsquamous cell lung cancer [85], pancreatic cancer [86], and neurofibroma [87,88].”
BackgroundModing, E. J., Castle, K. D., Perez, B. A., Oh, P., Min, H. D., Norris, H., Ma, Y., Cardona, D. M., Lee, C., & Kirsch, D. G. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa4214 · Cited by 93 · see citing works
Self-citationWitkiewicz, A. K., Balaji, U., Eslinger, C. R., McMillan, E. A., Conway, W. C., Posner, B. A., Mills, G. B., O'Reilly, E. M., & Knudsen, E. S. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.07.023 · Cited by 93 · see citing works
“Empirical approaches to uncovering combination therapy sensitivities have proved successful in defining new treatment strategies (Chen et al., 2012; Crystal et al., 2014; Vora et al., 2014).”
BackgroundZhang, W., Gao, Y., Li, F., Tong, X., Ren, Y., Han, X., Yao, S., Long, F., Yang, Z., Fan, H., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-3396 · Cited by 93 · see citing works
“Loss of LKB1 contributes to more aggressive phenotypewith limited therapeutic options (8, 9, 33, 34).”
BackgroundNew cast for a new era: preclinical cancer drug development revisited
Herter-Sprie, G. S., Kung, A. L., & Wong, K. (2013) · Journal of Clinical Investigation · doi:10.1172/jci68340 · Cited by 91 · see citing works
Self-citationKaufman, J. M., Amann, J. M., Park, K., Arasada, R. R., Li, H., Shyr, Y., & Carbone, D. P. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000173 · Cited by 87 · see citing works
“In vivo testing of treatment regimens demonstrates that these murine tumors exhibit sensitivity to metabolic stress induced by phenformin(5) but are resistant to mitogen activated protein kinase pathway inhibition.(9) Although mouse models are useful tools for studying tumor biology, the validity of the Lkb1/ Kras lun…”
BackgroundCaicedo, C., García‐Velloso, M. J., Lozano, M. D., Labiano, T., Díaz, C. V., López-Picazo, J. M., Gúrpide, A., Zulueta, J. J., Richter, J. Á., & Perez‐Gracia, J. L. (2014) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-014-2833-4 · Cited by 91 · see citing works
“A recent study showed that mice harbouring tumours with KRAS and LKB1 or p53 mutations showed higher [(18)F]FDG uptake than those with only tumours with KRAS mutations [29].”
BackgroundStandardized decision support in next generation sequencing reports of somatic cancer variants
Dienstmann, R., Dong, F., Borger, D. R., Dias-Santagata, D. C., Ellisen, L. W., Le, L. P., & Iafrate, A. J. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.03.021 · Cited by 89 · see citing works
“(Chen et al., 2012; Shi et al., 2012; Wagle et al., 2011; Whittaker et al., 2013) 2.”
BackgroundWang, D. Y. Q., Pham, N., Tong, J., Sakashita, S., Allo, G., Kim, L., Yanagawa, N., Raghavan, V., Wei, Y., To, C., et al. (2016) · International Journal of Cancer · doi:10.1002/ijc.30472 · Cited by 89 · see citing works
- Authors
- 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., Peña, 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., Jänne, P. A., Pandolfi, P. P., Cantley, L. C., Kung, A. L., Engelman, J. A., & Wong, K.-K.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Loyola University Chicago (US)
- Iowa State University (US)
- University of North Carolina at Chapel Hill (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Scripps Research Institute (US)
- Massachusetts General Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Boston Children's Hospital (US)
- Corresponding author
- Kung, Andrew L.
- Engelman, Jeffrey A.
- Wong, Kwok-Kin
- ORCID
- Cheng, Katherine
- Walton, Zandra
- Wang, Yuchuan
- Ebi, Hiromichi
- Shimamura, Takeshi
- Liu, Yan
- Ouyang, Jing
- Gao, Peng
- Xu, Chunxiao
- Yanagita, Masahiko
- Wang, Shumei
- Lee, Charles
- Nakada, Yuji
- Sun, Yanping
- Franchetti, Yoko
- Cameron, Michael D.
- Nishino, Mizuki
- Hayes, D. Neil
- Wilkerson, Matthew D.
- Roberts, Patrick J.
- Lee, Carrie B.
- Bardeesy, Nabeel
- Butaney, Mohit
- Chirieac, Lucian R.
- Costa, Daniel B.
- Sharpless, Norman E.
- Demetri, George D.
- Pandolfi, Pier Paolo
- Cantley, Lewis C.
- Kung, Andrew L.
- Engelman, Jeffrey A.
- Wong, Kwok-Kin
- Venue
- Nature
- Published
- 2012-03
- Volume
- 483
- Issue
- 7391
- Pages
- 613-617
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3385933
- OpenAlex
- W2094207365
- Cited by
- 446
- References
- 30
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 8 · 2023: 27 · 2022: 13 · 2021: 30 · 2020: 21 · 2019: 29 · 2018: 31 · 2017: 35 · 2016: 42 · 2015: 55 · 2014: 58 · 2013: 62 · 2012: 18
- FWCI
- 49.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- American Lung Association
- National Institutes of Health (5k23ca157631-02)
- National Cancer Institute (CA137181, R01CA166480, K23-CA157631, RC2CA147940, R01CA122794, R01CA140594, CA 140594, P50CA090578, CA147940, CA 122794, R01CA137181, CA137008-01, R01CA163896, P01CA120964, R01CA137008, P30CA016086, U01CA141576, CA137008)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- lung cancer, KRAS-mutant lung cancer, co-clinical trials, docetaxel, selumetinib, MEK inhibitors, combination therapy, TP53 mutation, tumor suppressor loss, chemoresistance
- MeSH terms
- Docetaxel, Animals, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Disease Models, Animal, Drug Evaluation, Preclinical, Humans, Lung Neoplasms, Mutation, Pharmacogenetics, Proto-Oncogene Proteins, Tomography, X-Ray Computed, Biomarkers, Tumor, Reproducibility of Results, Randomized Controlled Trials as Topic, Genes, p53, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Clinical Trials, Phase II as Topic, Protein Serine-Threonine Kinases, ras Proteins, Fluorodeoxyglucose F18, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Taxoids, Positron-Emission Tomography, Mice, AMP-Activated Protein Kinases
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 ›
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