Abstract 523: Activating mutations in EGFR abrogate hypoxia-associated radiation resistance in non-small cell lung cancer

Abstract

Abstract Hypoxic tumors tend to be 3-5 times more resistant to ionizing radiation relative to well-oxygenated tumors in part because oxygen is required to stabilize radiation-induced DNA damage. Tumor-adaptive responses also contribute to hypoxia-associated radioresistance but the precise mechanisms are not fully understood. Here we test our evidence-based hypothesis that the epidermal growth factor receptor (EGFR), which is frequently over-expressed in non-small cell lung carcinomas (NSCLCs), has critical roles in a tumor adaptive DNA damage response (DDR) pathway in hypoxic tumors. We find that, despite elevated EGFR activity and pro-survival signaling, hypoxia-associated radioresistance is dramatically reduced in a biologically distinct class of NSCLCs harboring activating mutations, L858R and ΔE746-E750 in EGFR. Hypoxic NSCLCs with EGFR mutations exhibit a unique spectrum of basal and hypoxia-induced DSBs not found in hypoxic wild type EGFR-expressing NSCLCs. These lesions dominate the S-phase of the cell cycle and are linked to collapsed replication forks in hypoxic cells. Replication fork-associated DSBs are repaired in wild type, but not in mutant, EGFR expressing NSCLCs. Microarray gene expression analysis revealed that mutant, but not wild type, EGFR expression results in an altered DDR characterized by dramatic down-regulation of several key components of the HR pathway within 24 hours of exposure to 0.1% oxygen. Our model predicts that NHEJ, not HR, dominates an altered DDR in hypoxic tumors. Elevated EGFR signaling may contribute to this altered DDR state where the EGFR-NHEJ axis becomes critical for hypoxia associated radioresistance and could be a potential target for hypoxic tumor radiosensitization. Citation Format: Mohammad Saki, Haruhiko Makino, Nozomi Tomimatsu, Lianghao Ding, Michael D. Story, Sandeep Burma, Chaitanya Nirodi. Activating mutations in EGFR abrogate hypoxia-associated radiation resistance in non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 523.