Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
Nat Commun. 2022 Apr 22;13(1):2206. doi: 10.1038/s41467-022-29905-1.
Targeting ferroptosis, a unique cell death modality triggered by unrestricted lipid peroxidation, in cancer therapy is hindered by our incomplete understanding of ferroptosis mechanisms under specific cancer genetic contexts. KEAP1 (kelch-like ECH associated protein 1) is frequently mutated or inactivated in lung cancers, and KEAP1 mutant lung cancers are refractory to most therapies, including radiotherapy. In this study, we identify ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells. We further show that pharmacological inhibition of the CoQ-FSP1 axis sensitizes KEAP1 deficient lung cancer cells or patient-derived xenograft tumors to radiation through inducing ferroptosis. Together, our study identifies CoQ-FSP1 as a key downstream effector of KEAP1-NRF2 pathway and as a potential therapeutic target for treating KEAP1 mutant lung cancers.
针对铁死亡，一种由不受限制的脂质过氧化引发的独特细胞死亡方式，在癌症治疗中受到限制，因为我们对特定癌症遗传背景下的铁死亡机制的理解还不完全。KEAP1（kelch-like ECH associated protein 1）在肺癌中经常发生突变或失活，KEAP1 突变型肺癌对大多数治疗方法（包括放疗）都有抗药性。在这项研究中，我们将铁死亡抑制蛋白 1（FSP1，也称为 AIFM2）鉴定为核因子红细胞 2 相关因子 2（NRF2）的转录靶点，并揭示了泛醌（CoQ）-FSP1 轴在 KEAP1 缺陷型肺癌细胞中介导铁死亡和辐射抗性。我们进一步表明，通过诱导铁死亡，药理学抑制 CoQ-FSP1 轴可使 KEAP1 缺陷型肺癌细胞或患者来源的异种移植肿瘤对放疗敏感。总之，我们的研究确定了 CoQ-FSP1 作为 KEAP1-NRF2 通路的关键下游效应因子，并作为治疗 KEAP1 突变型肺癌的潜在治疗靶点。
