title: EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune infiltration in EGFR mutant transgenic mouse models.
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.
authors: Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors: Abhilash
authors: A
authors: Venugopalan
authors: Developmental Therapeutics Branch, National Cancer Institute, Bethesda, MD, USA.
authors: Min-Jung
authors: MJ
authors: Lee
authors: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD, USA.
authors: Gang
authors: G
authors: Niu
authors: Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors: José
authors: J
authors: Medina-Echeverz
authors: Developmental Therapeutics Branch, National Cancer Institute, Bethesda, MD, USA.
authors: Yusuke
authors: Y
authors: Tomita
authors: Mouse Imaging Facility, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors: Martin J
authors: MJ
authors: Lizak
authors: Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors: Constance M
authors: CM
authors: Cultraro
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors: Robert Mark
authors: RM
authors: Simpson
authors: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD, USA.
authors: Xiaoyuan
authors: X
authors: Chen
authors: Developmental Therapeutics Branch, National Cancer Institute, Bethesda, MD, USA.
authors: Jane B
authors: JB
authors: Trepel
authors: Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors: Udayan
authors: U
authors: Guha
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000068818:Cetuximab / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: EGFR; TKI; imaging; immune-infiltration; lung cancer