Tumor hypoxia promotes acquired resistance to radiation through ferroptosis inhibition

点击翻译按钮获取中文摘要

Project 2 Summary Tumor hypoxia, defined as low intratumoral oxygen tension, is common to most solid malignancies, including lung and esophageal cancer. Lung and esophageal cancer treatments include radiation therapy (RT); however, clinically, these cancers develop acquired resistance to RT. The mechanisms of acquired resistance to RT are unknown but may involve a type of cell death called ferroptosis, which is the overarching theme of the proposed Acquired Resistance to Therapy and Iron (ARTI) Center. Project 2 will contribute to this overarching theme by determining whether hypoxia drives ferroptosis resistance, thereby promoting the acquired resistance to RT. Project 2 will utilize lung and esophageal cancer cell lines generated in Project 1 that are deficient in the ferroptosis resistance-mediator Solute Carrier Family 7 Member 11 (SLC7A11) and one of its transcription factors: activating transcription factor 4 (ATF4). The transcription of genes, including hypoxia-related genes, may be dynamically regulated within tumor cells and cells of the tumor microenvironment during chemoradiation therapy (CRT) of esophageal adenocarcinoma, which is a focus of Project 3. In order to determine whether oxygen is required for ferroptosis induction by RT, lung and esophageal cancer cells will be subjected to varying oxygen concentrations and radiosensitivity, lipid peroxidation (i.e., driver of ferroptosis), and SLC7A11 expression will be measured (Aim 1). Aim 2 will focus on the delineation of the mechanisms of hypoxia-driven ferroptosis resistance during acquired RT resistance by determining whether SLC7A11 expression is dependent on ATF4 under hypoxic conditions during RT. Furthermore, as hypoxia inducible factors (HIFs) have been shown to promote radioresistance, the effect of hypoxia-induced HIF activation in acquired resistance to ferroptosis will be investigated. To test the hypothesis that enhanced tumor oxygenation through hyperbaric oxygen treatment (HBOT) as well as small molecule HIF and ATF4 inhibitors can overcome acquired radioresistance by enhancing ferroptosis induction, lung tumor and esophageal tumor xenografts in mice will be treated with RT in combination with HBOT or HIF/ATF4inhibitors(Aim 3). Tumor growth after RT will be monitored with weekly noninvasive bioluminescence imaging at the Molecular Imaging Core (MIC). Furthermore, in the MIC, hypoxic regions within tumors will be monitored in real-time by performing positron emission tomography (PET) using the PET tracer 18F-Fluoroazomycin arabinoside (FAZA). Overall, the differential regulation of ferroptosis and acquired RT resistance by poorly oxygenated and well oxygenated areas in tumors discovered in Project 2 will iteratively strengthen and support the basic science/mechanistic Project 1 and the preclinical/translational Project 3 by helping identify tumor regions that may develop acquired resistance to RT that could aid in patient selection for subsequent treatments.