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Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune
Abhilash Venugopalan1, Min-Jung Lee2, Gang Niu3
1Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
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.
Insights
Early effects of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma models show rapid tumor regression and immune system activation. Resistance mechanisms were identified, guiding combination therapy strategies.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Lung adenocarcinoma patients with EGFR mutations benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs).
- Objective response to TKIs is typically seen after 6-8 weeks, with 30-40% of patients exhibiting intrinsic resistance.
- Understanding immediate-early treatment effects is crucial for optimizing TKI therapy and overcoming resistance.
Purpose of the Study:
- To investigate the immediate-early effects of EGFR-TKI treatment on tumors and the tumor microenvironment in mutant EGFR-driven lung adenocarcinoma mouse models.
- To correlate imaging findings with molecular and cellular changes within the tumor.
- To explore therapeutic strategies for TKI-resistant lung adenocarcinoma.
Main Methods:
- Utilized transgenic mouse models of lung adenocarcinoma with specific EGFR mutations (EGFRL858R and EGFRL858R/T790M).
- Administered erlotinib and afatinib (alone and in combination with cetuximab) and assessed tumor response using FDG-PET and MRI within 24 hours.
- Correlated imaging data with downstream EGFR signaling, apoptosis, proliferation, and immune cell infiltration (CD45+, NK cells, dendritic cells, macrophages, lymphocytes, CD8+ T cells) and MHC class II expression.
Main Results:
- Erlotinib treatment led to ~65% tumor regression within 24 hours in EGFRL858R-driven tumors.
- EGFRL858R/T790M tumors showed resistance to monotherapy but responded to afatinib-cetuximab combination.
- Imaging responses correlated with inhibited EGFR signaling, increased apoptosis, decreased proliferation, and significant immune cell infiltration, including enhanced antigen-presenting capacity of dendritic cells and macrophages.
Conclusions:
- Immediate-early imaging can predict therapeutic response to EGFR TKIs in lung adenocarcinoma.
- Combination therapy with afatinib and cetuximab can overcome TKI resistance mediated by the T790M mutation.
- EGFR TKIs induce significant changes in the tumor immune microenvironment, enhancing anti-tumor immunity.
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