Oncotarget

Priority Research Papers:

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

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

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Oncotarget. 2016; 7:54137-54156. https://doi.org/10.18632/oncotarget.11021

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Abstract

Abhilash Venugopalan1, Min-Jung Lee2, Gang Niu3, José Medina-Echeverz1, Yusuke Tomita2, Martin J. Lizak4, Constance M. Cultraro1, Robert Mark Simpson5, Xiaoyuan Chen3, Jane B. Trepel2 and Udayan Guha1

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 EGFRL858R lung adenocarcinoma. However, mice with EGFRL858R/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 EGFRL858R-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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