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R. Ruo
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-108 - Differential Cellular and Molecular Response to Ablative Radiation in Non-Small Cell Lung Cancer Based on Molecular Subtype (ID 2281)
09:30 - 09:30 | Author(s): R. Ruo
- Abstract
Background:
Ablative radiotherapy (ART) is increasingly used in the management and treatment of early-stage inoperable non-small cell lung cancer (NSCLC). Clinical studies show response rates of 80-90% in NSCLC patients treated with ART. However, the cellular and molecular determinants of the response to ART have not been investigated and recent analysis of patterns of failure in patients treated with ART show increased distant metastatic recurrence.
Methods:
Human NSCLC adenocarcinoma cell lines with different molecular subtypes (EGFR, K-RAS and p53 status) were chosen for this study including, A549, HCC827 and H1975 cells. To assess the cellular response to ART, several cellular assays were used after exposure to a single dose of 12Gy. Western blotting was performed to analyze expression and phosphorylation levels of molecular determinants involved in proliferation and invasion after exposure to ART. An In vivo study was performed using a novel orthotopic primary NSCLC animal model. When lung tumors reached a size of 0.2 cm[3], animals were treated with a dose of 34Gy using a Varian Novalis system equipped with cone-beam CT for accurate positioning. Treated animals were sacrificed at 10days, 30days and 60days after treatment and assessed for the presence of local and distant metastasis. In addition, immunohistochemistry was performed to assess tumor markers for proliferation, invasiveness, and metastasis.
Results:
Our results show that ART significantly reduced cell proliferation compared to FRT in A549 cells only. HCC827 and H1975 cells were equally inhibited by ablative and fractionated radiation. In A549 cells, ART significantly increased the invasive phenotype of the cells while in HCC827 and H1975 cell invasion was significantly reduced compared to FRT. Molecular analysis of proteins involved in invasion and migration revealed that ART upregulated c-MET expression in A549 cells without inducing epithelial-to-mesenchymal transition (EMT). In tumor-bearing rats, 50% had complete response, 25% partial response and 25% had local progression or distant metastasis after 34Gy. Consistent with in-vitro data, the tumor invasive profile was independent of EMT.
Conclusion:
Our results demonstrate that there is a differential response to ablative and fractionated radiation that is cell-type dependent. A549 cells exposed to ablative doses acquired a pro-invasive and migratory phenotype, which was independent of EMT. These findings can have significant implications for NSCLC patients undergoing ART and underscore the importance of understanding the underlying biology for effective disease management and treatment.
