Ferroptosis resistance as a key driver in acquired radiation resistance

项目1摘要 铁下垂是一种调节细胞死亡的形式，由铁依赖的脂质引发。 过氧化。我们和其他人之前的研究发现，铁性下垂是一种关键的肿瘤抑制 机制，并表明，诱发铁性下垂有望用于癌症治疗。最近，我们和 其他研究表明，放射治疗(RT)可以有效地诱发下垂，并确定了下垂的诱因。 (FINS)作为具有内在辐射抵抗的肿瘤(如Keap1或P53突变肿瘤)的放射增敏剂。 然而，铁性下垂的机制和治疗与获得性放射抵抗的相关性仍然存在。 很大程度上是未被开发的。我们的长期目标是了解获得性上睑下垂的发病机制。 获得性耐药与疾病复发的治疗耐药及合理靶向铁性下垂 癌症治疗。本申请的目标是确定通过哪些机制 铁下垂抵抗与胸癌(包括肺癌和肺癌)获得性放射抵抗有关 食道癌)，并评估FINS作为克服后天获得性疾病的治疗策略 这些癌症中的辐射抵抗。我们的初步数据支持以下中心假设：(I)铁性下垂 耐药是肺部获得性放射抵抗的关键机制 食道癌和(Ii)FINS和免疫疗法相结合是治疗食道癌的有效策略 克服获得性辐射抵抗，而不会对正常组织造成重大损害。测试我们的 假设，我们将追求以下具体目标：具体目标1.通过以下方式定义机制 铁下垂抵抗驱动获得性辐射抵抗。具体目标2.确定 FINS联合RT在克服获得性肿瘤放射抵抗中的有效性。具体目标3.至 确定FINS对正常细胞和组织辐射毒性的潜在影响。它是 期望我们提出的研究将确定铁下垂和获得性辐射抵抗的新机制。 并找出有效的新治疗策略来克服胸部获得性放射抵抗 癌症治疗。我们的提案极具创新性，因为它侧重于以前未探索过的 将铁下垂与获得性辐射抵抗联系起来的途径。我们提议的研究将具有重要的意义 影响我们对铁性下垂基本机制和治疗耐药的认识 以及我们在癌症治疗中针对获得性放射抵抗中铁下垂的能力。

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.