EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune infiltration in EGFR mutant transgenic mouse models
| Autor: | Min-Jung Lee, Udayan Guha, Robert Mark Simpson, José Medina-Echeverz, Jane B. Trepel, Xiaoyuan Chen, Abhilash Venugopalan, Gang Niu, Constance M. Cultraro, Yusuke Tomita, Martin J. Lizak |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Lung Neoplasms EGFR Afatinib medicine.medical_treatment Cetuximab Adenocarcinoma of Lung Apoptosis Adenocarcinoma Targeted therapy Erlotinib Hydrochloride Mice 03 medical and health sciences T790M 0302 clinical medicine medicine Animals Humans Epidermal growth factor receptor Lung cancer Protein Kinase Inhibitors immune-infiltration Tumor microenvironment biology business.industry imaging Cancer medicine.disease TKI Xenograft Model Antitumor Assays respiratory tract diseases ErbB Receptors lung cancer 030104 developmental biology Oncology Positron-Emission Tomography 030220 oncology & carcinogenesis Mutation Cancer research biology.protein Erlotinib business Priority Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.11021 |
| Popis: | // Abhilash Venugopalan 1 , Min-Jung Lee 2 , Gang Niu 3 , Jose 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 . |
| Databáze: | OpenAIRE |
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