Targeting CX3CR1 Suppresses the Fanconi Anemia DNA Repair Pathway and Synergizes with Platinum.
Targeting CX3CR1 Suppresses the Fanconi Anemia DNA Repair Pathway and Synergizes with Platinum.
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DOI：
10.3390/cancers13061442
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发表时间：
2021-03-22
期刊：
影响因子：
5.2
通讯作者：
Gustafsson NMS
中科院分区：
文献类型：
--
作者：
Lehto J;Huguet Ninou A;Chioureas D;Jonkers J;Gustafsson NMS
通过引入DNA交联而发挥其抗增殖作用的化疗剂，如铂类药物，被用于治疗多种癌症。不幸的是，它们的治疗潜力是有限的，由于不良的副作用和获得性耐药性，后者往往与增强的DNA修复能力。因此，靶向DNA修复是降低有效剂量和相关副作用以及恢复对治疗的敏感性的有希望的策略。C-X3-C基序趋化因子受体1（CX 3CR 1）是一种新兴的抗癌靶点，其表达与接受DNA损伤治疗的癌症患者的总体生存率较差相关。在这里，我们首次证明了靶向CX 3CR 1的临床阶段小分子抑制剂KAND 567通过干扰范可尼贫血DNA修复途径，增强了DNA交联化疗药物在癌细胞系（包括铂耐药模型）中的疗效。因此，CX 3CR 1和FA修复之间的相互作用为用DNA交联剂治疗的癌症提供了新的潜在治疗机会。C-X3-C基序趋化因子受体1（CX 3CR 1，fractalkine受体）与肿瘤转化，炎症，神经退行性疾病和衰老相关，靶向CX 3CR 1（CX 3CR 1 i）的小分子抑制剂KAND 567在临床试验中评估了SARS-CoV-2感染后的急性全身性炎症。在这里，我们确定了一个迄今为止未知的作用CX 3CR 1范可尼贫血（FA）途径介导的DNA链间交联（ICLs）在复制细胞的修复。FA通路激活触发CX 3CR 1核定位，这促进关键FA蛋白FANCD 2组装成病灶。在ICL诱导后干扰CX 3CR 1功能导致复制细胞无法从S期进展，复制叉停滞和关键FA途径因子的染色质募集受损。与缺陷性FA修复一致，CX 3CR 1 i导致残留顺铂-DNA加合物水平增加和细胞存活率降低。重要的是，CX 3CR 1 i在增殖试验（包括铂耐药模型）中以不可逆方式与铂剂协同作用。总之，我们的研究结果揭示了CX 3CR 1和FA通路之间的意外相互作用，并首次表明靶向CX 3CR 1的临床阶段小分子抑制剂可能在改善对DNA交联化疗药物的反应方面表现出益处。
Chemotherapeutics exerting their antiproliferative actions by introducing DNA crosslinks, such as platinum drugs, are used to treat numerous cancers. Unfortunately, their therapeutic potential is limited due to adverse side effects and acquired resistance, the latter often associated with enhanced DNA repair capacity. Thus, targeting DNA repair is a promising strategy to lower effective doses and associated side effects, and to restore sensitivity to treatment. The C-X3-C motif chemokine receptor 1 (CX3CR1) is an emerging anticancer target which expression correlates with worse overall survival in cancer patients undergoing DNA damaging treatments. Here we show for the first time that the clinical-phase small molecule inhibitor KAND567 targeting CX3CR1 augments the efficacy of DNA crosslinking chemotherapeutics in cancer cell lines, including platinum resistant models, by interference of the Fanconi anemia DNA repair pathway. Hence, the interplay between CX3CR1 and FA repair provides novel potential therapeutic opportunities in cancers treated with DNA crosslinking agents. The C-X3-C motif chemokine receptor 1 (CX3CR1, fractalkine receptor) is associated with neoplastic transformation, inflammation, neurodegenerative diseases and aging, and the small molecule inhibitor KAND567 targeting CX3CR1 (CX3CR1i) is evaluated in clinical trials for acute systemic inflammation upon SARS-CoV-2 infections. Here we identify a hitherto unknown role of CX3CR1 in Fanconi anemia (FA) pathway mediated repair of DNA interstrand crosslinks (ICLs) in replicating cells. FA pathway activation triggers CX3CR1 nuclear localization which facilitates assembly of the key FA protein FANCD2 into foci. Interfering with CX3CR1 function upon ICL-induction results in inability of replicating cells to progress from S phase, replication fork stalling and impaired chromatin recruitment of key FA pathway factors. Consistent with defective FA repair, CX3CR1i results in increased levels of residual cisplatin-DNA adducts and decreased cell survival. Importantly, CX3CR1i synergizes with platinum agents in a nonreversible manner in proliferation assays including platinum resistant models. Taken together, our results reveal an unanticipated interplay between CX3CR1 and the FA pathway and show for the first time that a clinical-phase small molecule inhibitor targeting CX3CR1 might show benefit in improving responses to DNA crosslinking chemotherapeutics.
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影响因子：
16.6
作者：
Liang CC;Li Z;Lopez-Martinez D;Nicholson WV;Vénien-Bryan C;Cohn MA
通讯作者：
Cohn MA
影响因子：
9.8
作者：
McQuin C;Goodman A;Chernyshev V;Kamentsky L;Cimini BA;Karhohs KW;Doan M;Ding L;Rafelski SM;Thirstrup D;Wiegraebe W;Singh S;Becker T;Caicedo JC;Carpenter AE
通讯作者：
Carpenter AE
影响因子：
8.8
作者：
Mutreja K;Krietsch J;Hess J;Ursich S;Berti M;Roessler FK;Zellweger R;Patra M;Gasser G;Lopes M
通讯作者：
Lopes M
影响因子：
16
作者：
Paulsen, Renee D.;Soni, Deena V.;Wollman, Roy;Hahn, Angela T.;Yee, Muh-Ching;Guan, Anna;Hesley, Jayne A.;Miller, Steven C.;Cromwell, Evan F.;Solow-Cordero, David E.;Meyer, Tobias;Cimprich, Karlene A.
通讯作者：
Cimprich, Karlene A.
影响因子：
20.3
作者：
Chen, Q;Van der Sluis, PC;Dalton, WS
通讯作者：
Dalton, WS