EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune infiltration in EGFR mutant transgenic mouse models

Venugopalan, Abhilash; Lee, Min-Jung; Niu, Gang; Medina-Echeverz, José; Tomita, Yusuke; Lizak, Martin J.; Cultraro, Constance M.; Simpson, Robert Mark; Chen, Xiaoyuan; Trepel, Jane B.; Guha, Udayan

doi:10.18632/oncotarget.11021

Cited by 40Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Diagnosis and Treatment

EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune infiltration in EGFR mutant transgenic mouse models

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Venugopalan, Abhilash, Lee, Min-Jung, Niu, Gang, Medina-Echeverz, José, Tomita, Yusuke, Lizak, Martin J., Cultraro, Constance M., Simpson, Robert Mark +3 more·2016·Oncotarget

DOI 10.18632/oncotarget.11021PMC PMC5338915

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// Abhilash Venugopalan 1 , Min-Jung Lee 2 , Gang Niu 3 , José Medina-Echeverz 1 , Yusuke Tomita 2 , Martin J. Lizak 4 , Constance M. Cultraro 1 , Robert Mark Simpson 5 , Xiaoyuan Chen 3 , Jane B. Trepel 2 and Udayan Guha 1 1 Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, USA 2 Developmental Therapeutics Branch, National Cancer Institute, Bethesda, MD, USA 3 Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD, USA 4 Mouse Imaging Facility, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD, USA 5 Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA Correspondence to: Udayan Guha, email: // Keywords : lung cancer, EGFR, TKI, imaging, immune-infiltration Received : May 23, 2016 Accepted : July 22, 2016 Published : August 02, 2016 Abstract Lung adenocarcinoma patients harboring kinase domain mutations in Epidermal growth factor receptor (EGFR) have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). Although a majority of patients experience clinical symptomatic benefit immediately, an objective response can only be demonstrated after 6-8 weeks of treatment. Evaluation of patient response by imaging shows that 30-40% of patients do not respond due to intrinsic resistance to these TKIs. We investigated immediate-early effects of EGFR-TKI treatment in mutant EGFR-driven transgenic mouse models by FDG-PET and MRI and correlated the effects on the tumor and the tumor microenvironment. Within 24 hours of erlotinib treatment we saw approximately 65% tumor regression in mice with TKI-sensitive EGFR L858R lung adenocarcinoma. However, mice with EGFR L858R/T790M -driven tumors did not respond to either erlotinib or afatinib monotherapy, but did show a significant tumor response to afatinib-cetuximab combination treatment. The imaging responses correlated with the inhibition of downstream EGFR signaling, increased apoptosis, and decreased proliferation in the tumor tissues. In EGFR L858R -driven tumors, we saw a significant increase in CD45 + leukocytes, NK cells, dendritic cells, macrophages and lymphocytes, particularly CD8 + T cells. In response to erlotinib, these dendritic cells and macrophages had significantly higher MHC class II expression, indicating increased antigen-presenting capabilities. Together, results of our study provide novel insight into the immediate-early therapeutic response to EGFR TKIs in vivo .

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Erlotinib upregulates MHC class II in DCs and macrophages, improving antigen presentation by immune cells.
“MHC class II upregulation by DCs and macrophages”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Venugopalan et al., 2016

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Additional file 4 of Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes
Dalens, L., Niogret, J., Richard, C., Chevrier, S., Foucher, P., Coudert, B. P., Lagrange, A., Favier, L., Westeel, V., Kim, S., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23804864
Additional file 3 of Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes
Dalens, L., Niogret, J., Richard, C., Chevrier, S., Foucher, P., Coudert, B. P., Lagrange, A., Favier, L., Westeel, V., Kim, S., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23804861
Additional file 2 of Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes
Dalens, L., Niogret, J., Richard, C., Chevrier, S., Foucher, P., Coudert, B. P., Lagrange, A., Favier, L., Westeel, V., Kim, S., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23804858
Additional file 8 of Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes
Dalens, L., Niogret, J., Richard, C., Chevrier, S., Foucher, P., Coudert, B. P., Lagrange, A., Favier, L., Westeel, V., Kim, S., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23804876
Additional file 1 of Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes
Dalens, L., Niogret, J., Richard, C., Chevrier, S., Foucher, P., Coudert, B. P., Lagrange, A., Favier, L., Westeel, V., Kim, S., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23804855
Additional file 6 of Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes
Dalens, L., Niogret, J., Richard, C., Chevrier, S., Foucher, P., Coudert, B. P., Lagrange, A., Favier, L., Westeel, V., Kim, S., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23804870
Additional file 7 of Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes
Dalens, L., Niogret, J., Richard, C., Chevrier, S., Foucher, P., Coudert, B. P., Lagrange, A., Favier, L., Westeel, V., Kim, S., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23804873
Additional file 5 of Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes
Dalens, L., Niogret, J., Richard, C., Chevrier, S., Foucher, P., Coudert, B. P., Lagrange, A., Favier, L., Westeel, V., Kim, S., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23804867

Abstract 725: In vivo imaging and quantitative proteomics to study responsiveness to EGFR targeted therapy.
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Abstract IA4: Defining the mechanisms of tumorigenesis by mutant EGFR using mouse models
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Lung adenocarcinomas induced in mice by mutant EGF receptors foundin human lung cancers respondto a tyrosine kinase inhibitor orto down-regulation of the receptors
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EGFR-TKI acquired resistance in lung cancers harboring EGFR mutations in immunocompetent C57BL/6J mice
Higo, H., Ohashi, K., Makimoto, G., Nishii, K., Kudo, K., Kayatani, H., Watanabe, H., Kano, H., Ninomiya, K., Hotta, K., et al. (2019) · Lung Cancer · doi:10.1016/j.lungcan.2019.08.019 · Cited by 13 · see citing works

Authors: Venugopalan, A., Lee, M.-J., Niu, G., Medina-Echeverz, J., Tomita, Y., Lizak, M. J., Cultraro, C. M., Simpson, R. M., Chen, X., Trepel, J. B., & Guha, U.
Affiliations: National Institutes of Health (US)
National Institute of Biomedical Imaging and Bioengineering (US)
Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, USA
National Cancer Institute (US)
Corresponding author: Guha, Udayan
ORCID: Venugopalan, Abhilash
Lee, Min-Jung
Niu, Gang
Tomita, Yusuke
Cultraro, Constance M.
Chen, Xiaoyuan
Trepel, Jane B.
Guha, Udayan
Venue: Oncotarget
Publisher: Impact Journals, LLC
Published: 2016-08-02
Volume: 7
Issue: 34
Pages: 54137-54156
ISSN: 1949-2553 (ISSN-L)
DOI: 10.18632/oncotarget.11021
PMC: PMC5338915
OpenAlex: W2479511981
Cited by: 40
References: 52
Citations by year: 2026: 1 · 2025: 3 · 2024: 1 · 2023: 12 · 2022: 6 · 2021: 7 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 2
FWCI: 2.09
Type: journal article
Language: en
Open access: diamond
doi.org
Licence: cc-by
Locations: Oncotarget (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Lung Cancer Research Foundation
Memorial Sloan-Kettering Cancer Center
Frederick National Laboratory for Cancer Research
National Institutes of Health
National Cancer Institute
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords: anti-EGFR therapy, tyrosine kinase inhibitors, lung adenocarcinoma, L858R mutation, T790M mutation, erlotinib, afatinib, cetuximab, combination therapy, tumor microenvironment, immune cell infiltration, FDG-PET imaging, magnetic resonance imaging, transgenic mouse model
MeSH terms: Cetuximab, Erlotinib Hydrochloride, Adenocarcinoma of Lung, Adenocarcinoma, Animals, Humans, Lung Neoplasms, Mutation, Apoptosis, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors, Positron-Emission Tomography, Mice, ErbB Receptors

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EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune infiltration in EGFR mutant transgenic mouse models

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