A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers.
A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers.
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靶向辅酶Q-FSP1轴驱动铁下垂和辐射抵抗Keap1非活动性肺癌。
DOI：
10.1038/s41467-022-29905-1
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发表时间：
2022-04-22
影响因子：
16.6
通讯作者：
Gan, Boyi
中科院分区：
文献类型：
--
作者：
Koppula, Pranavi;Lei, Guang;Zhang, Yilei;Yan, Yuelong;Mao, Chao;Kondiparthi, Lavanya;Shi, Jiejun;Liu, Xiaoguang;Horbath, Amber;Das, Molina;Li, Wei;Poyurovsky, Masha, V;Olszewski, Kellen;Gan, Boyi
针对ferroptosis，一个独特的细胞死亡模式引发的不受限制的脂质过氧化反应，在癌症治疗中受到阻碍，我们不完全理解的ferroptosis机制在特定的癌症遗传背景下。KEAP 1（kelch样ECH相关蛋白1）在肺癌中经常发生突变或失活，并且KEAP 1突变型肺癌对大多数治疗（包括放射治疗）都是难治的。在这项研究中，我们确定了铁凋亡抑制蛋白1（FSP 1，也称为AIFM 2）作为核因子红细胞2相关因子2（NRF 2）的转录靶点，并揭示了泛醌（CoQ）-FSP 1轴介导KEAP 1缺陷型肺癌细胞的铁凋亡和辐射抗性。我们进一步表明，对CoQ-FSP 1轴的药理学抑制通过诱导铁凋亡使KEAP 1缺陷型肺癌细胞或患者来源的异种移植肿瘤对辐射敏感。总之，我们的研究确定CoQ-FSP 1是KEAP 1-NRF 2通路的关键下游效应子，也是治疗KEAP 1突变型肺癌的潜在治疗靶点。KEAP 1突变在NSCLC中经常观察到，并导致耐药性。在这里，作者表明肺癌细胞中的KEAP 1突变通过NRF 2导致FSP 1上调，导致铁凋亡抗性和辐射抗性。
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. KEAP1 mutations are frequently observed in NSCLC and lead to drug resistance. Here, the authors show that KEAP1 mutations in lung cancer cells leads to FSP1 upregulation through NRF2, resulting in ferroptosis resistance and radioresistance.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
64.5
作者：
Basu A;Bodycombe NE;Cheah JH;Price EV;Liu K;Schaefer GI;Ebright RY;Stewart ML;Ito D;Wang S;Bracha AL;Liefeld T;Wawer M;Gilbert JC;Wilson AJ;Stransky N;Kryukov GV;Dancik V;Barretina J;Garraway LA;Hon CS;Munoz B;Bittker JA;Stockwell BR;Khabele D;Stern AM;Clemons PA;Shamji AF;Schreiber SL
通讯作者：
Schreiber SL
DOI：
10.1126/science.aaw9872
发表时间：
2020-04-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badgley MA;Kremer DM;Maurer HC;DelGiorno KE;Lee HJ;Purohit V;Sagalovskiy IR;Ma A;Kapilian J;Firl CEM;Decker AR;Sastra SA;Palermo CF;Andrade LR;Sajjakulnukit P;Zhang L;Tolstyka ZP;Hirschhorn T;Lamb C;Liu T;Gu W;Seeley ES;Stone E;Georgiou G;Manor U;Iuga A;Wahl GM;Stockwell BR;Lyssiotis CA;Olive KP
通讯作者：
Olive KP
同时发生的基因组改变对KRAS突变非小细胞肺癌患者结局的影响。
DOI：
10.1158/1078-0432.ccr-17-1841
发表时间：
2018-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arbour KC;Jordan E;Kim HR;Dienstag J;Yu HA;Sanchez-Vega F;Lito P;Berger M;Solit DB;Hellmann M;Kris MG;Rudin CM;Ni A;Arcila M;Ladanyi M;Riely GJ
通讯作者：
Riely GJ
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M