Journal
ONCOTARGET
Volume 7, Issue 34, Pages 54137-54156Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11021
Keywords
lung cancer; EGFR; TKI; imaging; immune-infiltration
Categories
Funding
- Intramural Research Program of the NIH / NCI / Center for Cancer Research (CCR)
- Lung Cancer Research Foundation (LCRF)
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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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