A PARP1 PROTAC as a novel strategy against PARP inhibitor resistance via promotion of ferroptosis in p53-positive breast cancer.
A PARP1 PROTAC as a novel strategy against PARP inhibitor resistance via promotion of ferroptosis in p53-positive breast cancer.
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PARP1 PROTAC 作为一种新策略，通过促进 p53 阳性乳腺癌中的铁死亡来对抗 PARP 抑制剂耐药性。
DOI：
10.1016/j.bcp.2022.115329
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发表时间：
2022-10
影响因子：
5.8
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Li G;Lin S;Yu Z;Wu X;Liu J;Tu G;Liu Q;Tang Y;Jiang Q;Xu J;Huang Q;Wu L
基于合成致死机制，用 PARP 抑制剂 (PARPis) 靶向核酶聚（ADP-核糖）聚合酶 1 (PARP1) 治疗同源重组 (HR) 缺陷表型患者，已在癌症治疗中取得了巨大成功。随着各种 PARPis 的临床使用，新的证据表明，无论 HR 状态如何，某些 PARPis 为三阴性乳腺癌 (TNBC) 治疗带来突破带来希望。然而，与其他常规细胞毒药物类似，PARPIs也面临着耐药性这一棘手问题。值得注意的是，目前的策略很难克服由 PARP1 蛋白点突变引起的对 PARPis 的获得性耐药。为了探索克服耐药性的方法并确定最有可能从 PARP1 靶向治疗中受益的患者，我们开发了一种蛋白水解靶向嵌合体 (PROTAC) 来降解 TNBC 中的突变 PARP1。在这里，我们研究了一种名为“NN3”的 PARP1 PROTAC，它触发了 PARP1 的泛素化和蛋白酶体介导的降解。此外，NN3 通过耐药相关突变降解 PARP1。有趣的是，与其他报道的 PARP1 降解剂相比，NN3 在 p53 阳性乳腺癌细胞中表现出独特的抗肿瘤机制，通过下调 SLC7A11 途径有效促进铁死亡。此外，NN3 显示出有效的活性和总之，我们提出 PROTAC 介导的 PARP1 降解作为对抗突变相关 PARPi 耐药性的新策略，以及通过铁死亡诱导以功能性 p53 靶向乳腺癌的范例。
Therapeutic targeting of the nuclear enzyme poly (ADP-ribose) polymerase 1 (PARP1) with PARP inhibitors (PARPis) in patients with a homologous recombination (HR)- deficient phenotype based on the mechanism of synthetic lethality has been shown tremendous success in cancer therapy. With the clinical use of various PARPis, emerging evidence has shown that some PARPis offer hope for breakthroughs in triple-negative breast cancer (TNBC) therapy, regardless of HR status. However, similar to other conventional cytotoxic drugs, PARPis are also subject to the intractable problem of drug resistance. Notably, acquired resistance to PARPis caused by point mutations in the PARP1 protein is hard to overcome with current strategies. To explore modalities to overcome resistance and identify patients who are most likely to benefit from PARP1-targeted therapy, we developed a proteolysis-targeted chimaera (PROTAC) to degrade mutant PARP1 in TNBC. Here, we investigated a PARP1 PROTAC termed “NN3″, which triggered ubiquitination and proteasome-mediated degradation of PARP1. Moreover,NN3degraded PARP1 with resistance-related mutations. Interestingly, compared with other reported PARP1 degraders,NN3exhibited a unique antitumor mechanism in p53-positive breast cancer cells that effectively promoted ferroptosis by downregulating the SLC7A11 pathway. Furthermore,NN3showed potent activity and low toxicity in vivo. In conclusion, we propose PROTAC-mediated degradation of PARP1 as a novel strategy against mutation-related PARPi resistance and a paradigm for targeting breast cancer with functional p53 via ferroptosis induction.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
4.9
作者：
Lee KJ;Mann E;Wright G;Piett CG;Nagel ZD;Gassman NR
通讯作者：
Gassman NR
影响因子：
8
作者：
Lei G;Zhang Y;Hong T;Zhang X;Liu X;Mao C;Yan Y;Koppula P;Cheng W;Sood AK;Liu J;Gan B
通讯作者：
Gan B
DOI：
10.1146/annurev-pathol-012414-040349
发表时间：
2016-05-23
期刊：
Annual review of pathology
影响因子：
--
作者：
Karni-Schmidt O;Lokshin M;Prives C
通讯作者：
Prives C
影响因子：
16
作者：
Erener, Sueheda;Petrilli, Virginie;Hottigert, Michael O.
通讯作者：
Hottigert, Michael O.