Ferroptosis resistance as a key driver in acquired radiation resistance

Project 1 Summary Ferroptosis is a form of regulated cell death that is triggered by iron-dependent lipid peroxidation. Previous studies by us and others identified ferroptosis as a critical tumor suppression mechanism and suggested that inducing ferroptosis holds promise for cancer treatment. Recently, we and others showed that radiotherapy (RT) can potently induce ferroptosis and identified ferroptosis inducers (FINs) as radiosensitizers to tumors with intrinsic radioresistance (such as KEAP1 or p53 mutant tumors). However, the mechanistic and therapeutic relevance of ferroptosis to acquired radioresistance remains largely unexplored. Our long-term goals are to understand the mechanistic basis of ferroptosis in acquired therapy resistance and to rationally target ferroptosis in acquired resistance and disease recurrence in cancer treatment. The objectives of this application are to determine the mechanisms by which ferroptosis resistance contributes to acquired radioresistance in thoracic cancers (including lung and esophageal cancers), and to assess FINs as a therapeutic strategy to overcome acquired radioresistance in these cancers. Our preliminary data support the central hypotheses that (i) ferroptosis resistance represents a key mechanism underlying acquired radioresistance in lung and esophageal cancers and (ii) combining FINs with immunotherapy is an effective therapeutic strategy to overcome acquired radioresistance without causing significant damage to normal tissues. To test our hypotheses, we will pursue the following specific aims: Specific Aim 1. To define the mechanisms by which ferroptosis resistance drives acquired radioresistance. Specific Aim 2. To determine the effectiveness of combining FINs with RT in overcoming acquired tumor radioresistance. Specific Aim 3. To determine the potential effects of FINs on radiation-induced toxicity in normal cells and tissues. It is expected that our proposed studies will identify novel mechanisms of ferroptosis and acquired radioresistance and identify effective new therapeutic strategies to overcome acquired radioresistance in thoracic cancer treatment. Our proposal is highly innovative because it focuses on previously unexplored pathways linking ferroptosis to acquired radioresistance. Our proposed studies will have a significant impact on both our understanding of the fundamental mechanisms of ferroptosis and therapy resistance and our ability to target ferroptosis in acquired radioresistance in cancer treatment.