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Introduction: Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancer cases. Nearly 70% of lung cancer patients will undergo radiotherapy (RT). Recent trends in RT have shown an increase in the use of ablative radiotherapy (ART) in inoperable small tumors with response rates of 80-90% in NSCLC patients. However, despite the high rate of local control, early clinical data shows no advantage in survival due to distant metastasis after ART compared to conventional fractionated radiotherapy (FRT). In addition, patient selection for ART is independent of the status of the epidermal growth factor receptor (EGFR) which has been shown to play a role in radiation response. We investigated the effect of ART compared to FRT on cell invasion, proliferation, senescence and clonogenic survival of NSCLC cell lines harboring wild type and mutated EGFR. Methods: The cell lines used were A549, H1975 and HCC827. Cell irradiation was performed using a Faxitron X-Ray machine. Radiation doses of 8Gy and12Gy were delivered in fractionated or single sessions. The effect of radiation on cells was investigated using the clonogenic assay, MTT proliferation assay, matrigel invasion assay and senescence-associated beta-galactosidase. Results: ART significantly suppressed the proliferative and clonogenic potential of wild-type EGFR A549 cells compared to FRT. In addition, a significant increase in the number of senescent as well as large, polynucleated cells was observed in the ART-treated group compared to the FRT-treated group. Analysis of the invasive potential of the cells revealed a 2-fold increase in invasion 5 days after exposure to ART of 12Gy compared to control. The FRT group showed a 1.4-fold increase in invasion compared to control. Contrary to A549 cells, EGFR-mutated NSCLC HCC827 and H1975 cells, showed no significant difference after exposure to ART compared to FRT. In addition, both ART and FRT-treated groups showed a similar increase in the number of senescent, large and polynucleated cells. A significant reduction in the number of invading cells after exposure to either FRT or ART was observed compared to the control. Conclusion: ART significantly reduces cell proliferation and clonogenic survival compared to FRT in wild-type EGFR A549 cells. This differential response between the type of treatment (ART vs FRT) was not seen in NSCLC cell lines harboring EGFR mutations. In contrast to reduced cell proliferation, there was a significant increase in the invasive capacity of cells after ART compared to FRT in A549 cells only. These results can have significant consequences in the selection and treatment of NSCLC patients for ART. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A66. Citation Format: Ayman J. Oweida, Jack Xu, Siham Sabri, Bassam Abdulkarim. Ablative radiotherapy increases invasion potential in EGFR-wildtype non-small cell lung cancer cells compared to fractionated radiotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A66.