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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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“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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Characterization of Torin2, an ATP-Competitive Inhibitor of mTOR, ATM, and ATR
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“In addition, our study highlights the growing awareness of the utility of GEMMs for preclinical drug studies [28,29].”
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“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
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“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].”
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“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…”
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“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
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“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).”
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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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