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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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ResultTranslational Therapeutics in Genetically Engineered Mouse Models of CancerPreprint
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Comparative mRNA and miRNA transcriptome analysis of a mouse model of IGFIR-driven lung cancer
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“The KP and KL GEMMs also demonstrate differences in tumor latency and metastatic propensity, as well as therapeutic sensitivity (9, 10).”
BackgroundClinicopathologic characteristics and outcomes for patients with KRAS G12D-mutant NSCLC
Cooper, A. J., Muzikansky, A., Lennerz, J., Narinesingh, F., Mino-Kenudson, M., Hung, Y. P., Piotrowska, Z., Dagogo-Jack, I., Sequist, L. V., Gainor, J. F., et al. (2022) · JTO Clinical and Research Reports · doi:10.1016/j.jtocrr.2022.100390 · Cited by 14
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“Recent development of lung cancer therapies has been largely aided in the pre-clinical space by the development of genetically engineered mouse models (GEMMs) [4 – 6] which carry genes with oncogenic mutations.”
BackgroundMouse models can predict cancer therapy
Kuehl, W. M. (2012) · Blood · doi:10.1182/blood-2012-04-422501 · Cited by 8
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“As a vital tumor suppressor, p53 expression is often lost in tumors, which can be directly correlated with the prognosis of patients [21].”
BackgroundA step towards treating KRAS-mutant NSCLC
Goldberg, S. B., Schlessinger, J., Boyer, J. L., & Herbst, R. S. (2012) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70528-4 · Cited by 8
Infrastructure Needs for Translational Integration of Mouse and Human TrialsPreprint
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“Studies that have established the effectiveness of this approach have recently led to the evolution of both coclinical and postclinical projects (Nardella et al. 2011; Chen et al, 2012; see also Lunardi et al. 2013).”
Preclinical and Coclinical Studies in Prostate CancerPreprint
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“Coclinical efforts have by now also shown significant promise toward a real-time optimization of patient stratification in the effective treatment of several other types of cancers (Chen et al. 2012, 2014; Kwong et al. 2015; Whitley et al. 2016).”
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“PTEN and STK11/LKB1 loss have been previously demonstrated to confer resistance to MEK and ERK inhibition ( 13 , 39 , 40 ), supporting the validity of our screen.”
ResultIf Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer
Köhler, J., & Janne, P. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22063025 · Cited by 7
“These tumors are linked to poor outcomes with immunotherapy and platinum-based chemotherapy [75,141,142].”
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“Addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but not in mice with Kras and Lkb1 muta‐ tions (Chen et al., 2012).”
BackgroundPatient-Derived Xenograft Models in Breast Cancer Research
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Genetic Mouse Models of Cancer
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“Here, we mapped global ATP-binding proteomes perturbed by two clinical MEK inhibitors, AZD6244 and MEK162, in KRAS mutant lung cancer cells as a model system harnessing a desthiobiotin-ATP probe coupled with LC-MS/MS.”
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“These comutations differentially alter signaling and metabolic pathways, subsequently affecting sensitivity to targeted therapies.(21,22) KRAS comutations also influence the tumor immune microenvironment and PD-L1 expression,(19,20,23,24) such that TP53 mutations have been associated with greater sensitivity to PD-(L)…”
BackgroundThe level of oncogenic Ras determines the malignant transformation of Lkb1 mutant tissue in vivo
Rackley, B. B., Seong, C.-S., Kiely, E. J., Parker, R. E., Rupji, M., Dwivedi, B., Heddleston, J. M., Giang, W., Anthony, N. R., Chew, T., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-01663-8 · Cited by 6
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“Preclinical studies suggest that cooccurring mutations may impact treatment responsiveness, since the treatment response to docetaxel monotherapy in lung tumors was markedly impaired when KRAS mutants cooccurred with TP53 mutations (40).”
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Exploring the Role and Mechanism of pAMPKα‐Mediated Dysregulation of Brf1 and RNA Pol III Genes
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“AMPK is a primary component of the LKB1 downstream pathway, while mutations of LKB1 are found in over 20% of patients with NSCLC and frequently associated with activating K-RAS mutations [26 – 28].”
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“Until a breakthrough is achieved with a direct pharmacologic approach, alternative strategies for addressing these undruggable targets remain under investigation [24].”
BackgroundExploration of Kras Mutations and Their Potential for Being a Target Molecule in Cancer Chemotherapy
Chinthareddy, A., & Oroszi, T. L. (2023) · Journal of Cancer Therapy · doi:10.4236/jct.2023.146022 · Cited by 5
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“In addition, CRISPR animal cancer models have become faithful models for testing various anti-cancer agents, as well as mechanisms of detecting drug resistance using CRISPR screening (Chen et al., 2012; Sánchez-Rivera and Jacks, 2015).”
BackgroundSelf-citationTargeting KRAS -Mutated NSCLC: Novel TKIs and Beyond
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“Despite these factors, ‘co-clinical trials’ have been performed where ‘xeno-patients’ have been used to test chemotherapeutic responses as a means to tailor a patient’s treatment programme [14].”
BackgroundKRAS et adénocarcinome bronchique. Entre déceptions et espoirs
Guibert, N. M., Ilié, M., Léna, H., Didier, A. P., Hofman, P. M., & Mazières, J. (2015) · Revue des Maladies Respiratoires · doi:10.1016/j.rmr.2015.05.012 · Cited by 4
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“Previous studies have shown that KRAS-mutated tumors harboring co-mutations in STK11 are often resistant to conventional treatment modalities consisting of chemotherapy and radiation (8-11).”
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“The success of regional “Mouse Hospitals” envisioned for global prevention and therapeutic trials involving mice (Chen et al. 2012) will require a much more rigorous use of searchable controlled and”
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“Of further interest is the fact that in a murine study of KRAS-mutant lung cancers, the presence of co-mutations in TP53 or STK11 (LKB1) impaired response to docetaxel and selumetinib (MEK inhibitor) when STK11 co-occurs as a mutation [20].”
Shared bias in H chain V-J pairing in naive and memory B cells
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Combined Micro-PET/Micro-CT Imaging of Lung Tumours in SPC-raf and SPC-myc Transgenic Mice
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“However, so far only few studies reported on micro-PET of spontaneously developing orthotopic lung tumours as opposed to xenograft models [15].”
BackgroundStromal Barriers Within the Tumor Microenvironment and Obstacles to Nanomedicine
Tanaka, H. Y., & Kano, M. R. (2019) · Springer eBooks · doi:10.1007/978-4-431-56880-3_4 · Cited by 3
Human Puf-A, a Novel Component of 90S Pre-ribosome, Links Ribosome Biogenesis to Cancer ProgressionPreprint
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“Ideally, studies of tumor pathophysiology in transgenic mice can complement clinical investigations by shedding light on unexpected therapy failure and facilitating the identification of corresponding biological markers (4), while using advanced imaging techniques developed for rodents.”
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Evolution of Clinical Trial Imaging and Co-clinical Imaging
Lee, A. J., Suh, C. H., & Kim, K. W. (2020) · Medical radiology · doi:10.1007/978-3-030-31171-1_14 · Cited by 2
Section IV: Non–small cell lung cancer and malignant melanoma
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Energizing the Search to Target LKB1-Mutant Tumors
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The use of biomarkers in the treatment of non-small cell lung cancer
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“[28,29] In a mouse model, it was found that lung”
BackgroundPatient-Derived Tumor Xenograft
Inghirami, G., Tinkey, P. T., de Stanchina, E., & Uthamanthil, R. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804010-2.00027-8 · Cited by 2
The next generation personalized models to screen hidden layers of breast cancer tumorigenicity
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Animal models and in vivo investigations for drug repurposing in lung cancer
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“One important result of the MMHCC projects was the formulation of the co-clinical trial concept [4].”
BackgroundSchmidt, D. R., Gramatikov, I. M. T., Sheen, A. M., Williams, C. L., Hurwitz, M., Dodge, L. E., Holupka, E. J., Kiger, W. S., Cornwall-Brady, M. R., Huang, W., et al. (2023) · Communications Medicine · doi:10.1038/s43856-023-00336-3 · Cited by 2
Preclinical Experimentation in Oncology
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Lundin, A., Porritt, M. J., Jaiswal, H., Seeliger, F., Johansson, C., Bidar, A. W., Badertscher, L., Davies, E. J., Hardaker, E. L., Martins, C. P., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.06.028803 · Cited by 2
“To demonstrate the utility of the ODInCas9 mouse NSCLC models for preclinical testing, efficacy studies based on previous clinical [26] and preclinical studies [27] were performed (Fig.”
MethodLopes, E. C., Sawant, A., Moore, D. F., Ke, H., Shi, F., Laddha, S. V., Chen, Y., Sharma, A., Naumann, J., Guo, J. Y., et al. (2023) · medRxiv · doi:10.1101/2023.03.09.23287037 · Cited by 2
“Proliferation (PI) and apoptotic (AI) indices were calculated a similar approach by considering 124 proliferation-associated genes (62) and six apoptosis-related genes.”
MethodSmall molecule activation of the tumor suppressor kinase LKB1Preprint
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JAK1/2 Inhibition Delays Cachexia and Improves Survival through Increased Food IntakePreprint
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Understanding and Overcoming Osteosarcoma Heterogeneity
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Small-molecule activation of the tumor suppressor kinase LKB1 via the pseudokinase STRAD
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Introduction to Ex Vivo Cancer Models
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Preclinical Organotypic Models for the Assessment of Novel Cancer Therapeutics and Treatment
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“Several studies show that GEMMs model both the TME and stroma more accurately than xenografts (Olive et al. 2009; Graves et al. 2010), and better replicate the sensitivity of cancer to systemic therapy in clinical trials (Singh et al. 2010; Chen et al. 2012).”
BackgroundMiscio, G., Paroni, G., Bisceglia, P., Gravina, C., Urbano, M., Lozupone, M., Piccininni, C., Prisciandaro, M., Ciavarella, G., Daniele, A., et al. (2019) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2019.1658742 · Cited by 1
“After the preliminary stages (animal models and Phase I trials) [157,158], PGx can help to draw useful data from variants that can potentially influence ADR, dosage, and efficacy.”
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Next generation personalized animals as an enabling technology in personalized vaccinology
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HUMANS, ANIMALS, AND PETRI DISHES: BIOMEDICAL MODELING BETWEEN EXPERIMENTATION AND REPRESENTATION
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Background
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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