The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
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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“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
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
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
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
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
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
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
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
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 615
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 578
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Items 401–446 of 446
Yang, C. (2014) · Digital Commons-TMC (Texas Medical Center) · Cited by 1
MEK inhibitor resistance in lung cancer cells associated with addiction to sustained ERK suppressionPreprint
Farnsworth, D., Inoue, Y., Johnson, F. D., de Rappard-Yuswack, G., Lu, D., Shi, R., Somwar, R., Ladanyi, M., Unni, A. M., & Lockwood, W. W. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.29.490009 · Cited by 1
“In mouse models of KRAS mutant lung cancer, MEK inhibitors display strong anti-tumor activity (15,16).”
BackgroundATE1 activates ER-stress and UPR pathways in glioblastomaPreprint
Macedo-da-Silva, J., Oba‐Shinjo, S. M., Rosa-Fernandes, L., Soares, R. D. S., Lerário, A. M., Moretti, I. F., Laurentino, T. D. S., Cintra, R. C., Marie, S. K. N., & Palmisano, G. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.25.559258 · Cited by 1
Using GEMMs to investigate novel therapeutic strategies for colorectal cancer
Raja, M. (2013) · ORCA Online Research @Cardiff (Cardiff University)
Preclinical Imaging in Oncology: Considerations and Recommendations for the Imaging Scientist
Bradley, D. P., & Wyant, T. L. (2013) · AAPS advances in the pharmaceutical sciences series · doi:10.1007/978-1-4614-8247-5_7
Predictive markers for chemotherapy response in breast cancer.
Steenkamer, M. (2012) · Utrecht University Repository (Utrecht University)
Thomas, A., López-Chávez, A., & Giaccone, G. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2015.62.7323
“Further extending these observations are reports that show the effect of coexisting mutations in determining response to the same targeted therapy, even among primary cancers that harbor identical genetic mutations.(3) In KRAS-mutant non–small-cell lung cancer, for example, therapeutic response to a combination of the…”
BackgroundTargeting Key Stemness-Related Pathways in Human Cancers
Coyle, K. M., Thomas, M. L., Sultan, M., & Marcato, P. (2015) · Springer eBooks · doi:10.1007/978-3-319-21030-8_15
Understanding and Using Information about Cancer Genomes
Spellman, P. T., Stuart, J. M., & Gray, J. W. (2015) · Elsevier eBooks · doi:10.1016/b978-1-4557-4066-6.00024-x
Abdel-Rahman, O. M. (2016) · Journal of Thoracic Disease · doi:10.21037/jtd.2016.06.72
“A number of MEK inhibitors have shown promise in preclinical models of KRAS-mutant NSCLC (like selumetinib and trametinib) (14-16).”
BackgroundZer, A., Tsao, M., & Shepherd, F. A. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.08.130
Yang, H. J., Yu, C., Li, Y., & Zhu, F. (2017) · Journal of Biosciences and Medicines · doi:10.4236/jbm.2017.53001
“The knowledge of these agents, their efficacy targets not only can be filled with numerous hurdles that call for targeted therapeutics [4] [5], How to cite this paper: Yang, H.”
BackgroundUse of precision methods to accelerate drug development in oncology
Coyne, G. O., Ivy, S. P., & Conley, B. A. (2017) · Expert Review of Precision Medicine and Drug Development · doi:10.1080/23808993.2017.1311773
“In contrast, the combination of docetaxel and selumetinib was effective in both the KRAS and KRAS–TP53 settings, whereas KRAS–STK11 tumors were resistant or less sensitive [71].”
ResultDirect in vivo mapping of functional suppressors in glioblastoma genomePreprint
Chow, R. D.-W., Guzman, C. D., Wang, G., Schmidt, F., Youngblood, M. W., Ye, L., Errami, Y., Dong, M. B., Martinez, M. A. Q., Zhang, S., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/153460
How to Promote and Organize Clinical Research in Lung Cancer
Barlési, F., Mazières, J., Zhou, Y., Herbst, R. S., & Zalcman, G. (2018) · Elsevier eBooks · doi:10.1016/b978-0-323-52357-8.00060-3
Molecular Mechanisms of Therapeutic Resistance in Cancer.
Wang, H. (2014) · Deep Blue (University of Michigan)
Satler, J. D., Carstens, B. C., & Hedin, M. C. (2015) · DRYAD · doi:10.5061/dryad.68s40.2/3.2
ENHANCING RADIATION SENSITIVITY IN NON-SMALL CELL LUNG CANCER
Wang, Y. (2018) · Digital Commons-TMC (Texas Medical Center)
Self-citationAn Overview of Preclinical Mouse Models for Brain Tumors
Ozawa, T. (2018) · Japanese Journal of Neurosurgery · doi:10.7887/jcns.27.752
Nagaraj, A. S. (2018) · Työväentutkimus Vuosikirja
Cao, W., Yan, C., Wang, H., Tang, T., Wang, H., & Liu, D. (2019) · Oncology Letters · doi:10.3892/ol.2019.10265
“A mouse model indicated that serine/threonine kinase 11‐deficient KRAS mutant NSCLC tumors were resistant to mitogen-activated protein kinase (MEK) inhibition, which may be clinically relevant (42,43).”
BackgroundHeat Shock Protein 90 Inhibitors in Lung Cancer Therapy
Chatterjee, S., & Burns, T. F. (2019) · Heat shock proteins · doi:10.1007/978-3-030-03952-3_19
Porcine model elucidates function of p53 isoform in carcinogenesisPreprint
Niu, G., Hellmuth, I., Flisikowska, T., Pausch, H., Rieblinger, B., Carrapeiro, A. R., Schade, B., Böhm, B., Kappe, E., Fischer, K., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.09.07.286005
Sánchez, J. M. P. (2021) · RiuNet (Universitat Politècnica de València) · doi:10.4995/thesis/10251/172736
Vuori, K., & Zhao, M. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.736274644.793566082
(2012) · Nature · doi:10.1038/492366a
Mechanisms of Resistance to Immunotherapies in Cancer
Lengyel, C. G. (2023) · Springer eBooks · doi:10.1007/978-3-030-80962-1_335-1
Akbay, E. A., Koyama, S., Carretero, J., Altabef, A. B., Tchaicha, J. H., Christensen, C. L., Mikse, O. R., Cherniack, A. D., Beauchamp, E. M., Pugh, T. J., et al. (2023) · doi:10.1158/2159-8290.22530261
Self-citationZhu, 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. (2023) · doi:10.1158/2159-8290.22529976
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) · doi:10.1158/2159-8290.c.6693745.v2
Lung cancer: Current status of preclinical research
Amoafo, E. B., Twum, E., Hottor, B. A., Fredua‐Agyeman, M., Kwapong, A. A., & Amponsah, S. K. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-31656-2.00005-0
PARP1 suppression drives ROS resistance in aneuploid cancer cells
Cheng, P., Mermerian, A., Wang, Y., Chen, Z., Quysbertf, H. M., Cheema, P. S., Mays, J. C., Zhao, X., Katsnelson, L., Mei, S., et al. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.04.006
Self-citationMechanisms of Resistance to Immunotherapies in Cancer
Lengyel, C. G. (2025) · Springer eBooks · doi:10.1007/978-3-032-00775-9_335
Touchscreen and Translational Cognition: A Systematic Review of Trials in Humans and Rodents
Martins, T. C., Santos, R. M. S., Andrade, R. K. D. S., da Silva, A. S., Brunheroto, F. B., Rocha, I. P. G., Loureiro, V. C. G., Silva, Y. C. D. S., Souza, A. C. N., de Souza, E. R., et al. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70297
“This review highlighted the importance of synchronous co-clinical trials, both to anticipate the outcomes of clinical studies in humans and to support the design and analysis of these studies (Chen et al. 2012).”
Molecular Regulators of Stem Cell Fate and Tumor Development in the Cerebellum
Brun, S. N. (2014) · DukeSpace (Duke University)
Sun, H., Ren, P., Chen, Y., Lan, L., Yan, Z., Yang, Y., Wang, B., Wang, C., Li, Y., Li, L., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22606069
Bondarenko, M. (2021) · theses.fr (ABES) · doi:10.70675/b6c8631azd6aaz42e9z9cf3z65208b9697a3
Laguerre, K. (2025) · theses.fr (ABES) · doi:10.70675/ec1d2832ze888z4203zb41czbf730fd69560
Targeting LKB1-inactivated lung cancers with a stapled peptide inhibitor of the CRTC-CREB pathway
Zhou, X., Bird, G. H., Yu, M., Li, J., Solone, X. K., Chung, M. C., Guan, J., Walensky, L. D., & Wu, L. (2026) · Molecular Therapy Oncology · doi:10.1016/j.omton.2026.201331
“17 27 Despite its prevalence and clinical significance, there are no effective therapies for LKB1-mutant NSCLC. LKB1 acts as a master kinase that activates AMPK and 12 AMPK-related kinases, including the salt-inducible kinases (SIKs).”
Self-citationMariano, M. P., Sgarilli, E., Mijnlieff, D., Visuvasam, B., Blesio, A., Digiacomo, G., Cavazzoni, A., Ferracin, M., & Giovannetti, E. (2026) · Cancer Drug Resistance · doi:10.20517/cdr.2026.52
Mutant p53 sensitizes KRAS-driven lung adenocarcinoma to immunotherapy by repressing SPP1
Zhang, X., Hao, Q., Yang, W., Yu, Y., Yan, Q., Wu, Z., Hu, Z., Zhou, X. Y., & Wang, J. (2026) · Science Advances · doi:10.1126/sciadv.aeg9953
Multifunctional nucleic acid-based therapy in fibrosis-related diseases
Cheng, J., Zhou, M., Guo, Y., Yang, Y., Lv, W., Renzeng, Y. A. N. G., Xie, Y., Jiang, Y., Yao, L., Qi, C., et al. (2026) · Science China Chemistry · doi:10.1007/s11426-025-3231-6
Mechanisms and Molecular Biology of Major Tumor Suppressors
Engel, B. E. (2014) · Digital Commons - University of South Florida (University of South Florida)
New Molecular Targets on the Horizon in Non-Small Cell Lung Cancer
Baumgart, M. A. (2015) · American Journal of Hematology / Oncology®
Metadata
- 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
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