Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer.
Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer.
复制标题
DOI：
10.1126/scitranslmed.aba4627
复制
发表时间：
2021-07-14
影响因子：
17.1
通讯作者：
Pardo OE
中科院分区：
文献类型：
--
作者：
Chrysostomou S;Roy R;Prischi F;Thamlikitkul L;Chapman KL;Mufti U;Peach R;Ding L;Hancock D;Moore C;Molina-Arcas M;Mauri F;Pinato DJ;Abrahams JM;Ottaviani S;Castellano L;Giamas G;Pascoe J;Moonamale D;Pirrie S;Gaunt C;Billingham L;Steven NM;Cullen M;Hrouda D;Winkler M;Post J;Cohen P;Salpeter SJ;Bar V;Zundelevich A;Golan S;Leibovici D;Lara R;Klug DR;Yaliraki SN;Barahona M;Wang Y;Downward J;Skehel JM;Ali MMU;Seckl MJ;Pardo OE
肺癌和膀胱癌由于早期出现耐药性和转移性扩散而大多无法治愈。因此，迫切需要更好的治疗方法来解决这两个过程，以改善临床结果。我们已经确定RSK 4作为肺癌和膀胱癌细胞中耐药性和转移的促进剂。通过RNA干扰或CRISPR沉默这种激酶，可以使肿瘤细胞对化疗敏感，并在尾静脉注射模型中阻碍体外和体内转移。药物筛选揭示了几种氟沙星抗生素作为有效的RSK 4活化抑制剂，并且曲伐他汀使用肺癌异种移植物和基因工程小鼠模型和膀胱肿瘤外植体在体外和体内/离体再现了RSK 4沉默的所有作用。通过X射线结构测定和马尔可夫瞬态和氘交换分析，我们确定了变构结合位点，并揭示了该化合物如何通过结合到变构位点并模拟涉及RSK 4疏水基序的激酶自抑制机制来阻断RSK 4激酶活化。最后，我们发现，在大型安慰剂对照、随机、3期SIGNIFICANT试验中，接受化疗并坚持预防性左氧氟沙星治疗的患者的长期总生存时间显著延长（p = 0.048）。因此，我们认为RSK 4抑制可能是治疗肺癌和膀胱癌的有效治疗策略。
Lung and bladder cancers are mostly incurable due to early development of drug resistance and metastatic dissemination. Hence, better therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, either through RNA interference or CRISPR, sensitised tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tailvein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically-engineered mouse models and bladder tumour explants. Through X-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase auto-inhibitory mechanism involving the RSK4’s hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomised phase 3 SIGNIFICANT Trial had significantly (p =0.048) increased long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.
登录
查看更多内容
影响因子：
2.9
作者：
Jacobson, MP;Pincus, DL;Friesner, RA
通讯作者：
Friesner, RA
影响因子：
6.4
作者：
Bender, Claus;Ullrich, Axel
通讯作者：
Ullrich, Axel
影响因子：
11.5
作者：
Herberger, Beata;Puhalla, Harald;Filipits, Martin
通讯作者：
Filipits, Martin
影响因子：
158.5
作者：
Cullen, M;Steven, N;Stanley, A
通讯作者：
Stanley, A
核糖体 s6 蛋白激酶 4：肾细胞癌的预后因素
影响因子：
8.8
作者：
Fan L;Li P;Yin Z;Fu G;Liao DJ;Liu Y;Zhu J;Zhang Y;Wang L;Yan Q;Guo Y;Shao C;Huang G;Wang Z
通讯作者：
Wang Z