Abstract 4174: Differential response of non-small cell lung cancer harboring different epidermal growth factor receptor mutations to ablative radiation therapy
Authors: Rabea Areej Al , Meehan Brian , Daniel Paul , Sabri Siham , Nirodi Chaitanya , Rak Janusz , Abdulkarim Bassam 
Published: August 2018

Background: ablative radiation therapy (ABR) serves as the treatment of choice for early stage non-small cell lung cancer (NSCLC) patients who are not surgical candidates. NSCLC patients with mutations in the tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) had a significant response to tyrosine kinase inhibitors (TYIs). The most common mutations of EGFR in NSCLC are present in the TKD domain and include: deletion (DEL) in the exon 19 and a missense mutation (L858R) in the exon 21. The role of extracellular vesicles (EVs) has been under extensive investigation due to its contribution in preparing the distant site through a process named pre-metastatic niche formation. Release of irradiation-induced EVs in EGFR mutated NSCLC and their responses to ABR have not been well investigated. We aim to assess EVs release and tumor growth of NSCLC harboring different EGFR mutations post- ABR. Materials and methods: We used A549 that were transduced with different EGFR status: EGFR-WT (WT), EGFR-DEL (DEL) or EGFR-L858R (L858R) and irradiated them at 0, 12 or 34Gy. The condition media were then collected at 24hrs post-irradiation and used to measure release of extracellular vesicles (EVs) using nanosight. We transduced the cells with lentivirus expressing luciferase. Cells were irradiated at 0Gy (Ctrl group) or 34Gy (IR group) and injected subcutaneously in yellow fluorescent protein -severe combined immunodeficiency (YFP-SCID) mice. Tumor volume and animal weight were measured regularly and bioluminescence imaging (BLI) was used to evaluate tumor growth and metastasis. Results: L858R-expressing cells had an increase in EVs release post-ABR (12 and 34Gy), compared to WT-expressing cells which did not have difference in EVs release following ABR. DEL-expressing cells had an increase in EVs release only at 34Gy. Furthermore, in vivo data revels that ABR caused a decrease in tumor growth of IR-WT and IR-DEL groups when compared to Ctrl-WT and Ctrl-DEL, respectively. Interestingly, both Ctrl-L858R and IR-L858R groups presented similar tumor growth. Further investigations are undergoing assessing the EVs release and their function in the occurrence of distant metastasis post-ABR. Conclusion: in our study, we report a differential response of non-small cell lung cancer to ABR that could be caused by the differences in EGFR status. As a result, the standard use of ABR should not only be based on the patients' comorbidity status, but should also be based on his/her genetic background in order to determine the optimal treatment.

Citation Format: Areej Al Rabea, Brian Meehan, Paul Daniel, Siham Sabri, Chaitanya Nirodi, Janusz Rak, Bassam Abdulkarim. Differential response of non-small cell lung cancer harboring different epidermal growth factor receptor mutations to ablative radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4174.