The WNK1-ERK5 route plays a pathophysiological role in ovarian cancer and limits therapeutic efficacy of trametinib.
The WNK1-ERK5 route plays a pathophysiological role in ovarian cancer and limits therapeutic efficacy of trametinib.
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DOI：
10.1002/ctm2.1217
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发表时间：
2023-04
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
晚期卵巢癌令人沮丧的预后要求开发新的治疗方法来改善疾病结局。在这方面，我们着手发现新的分子实体并评估其靶向的临床前有效性。使用了细胞系、小鼠和人卵巢癌样本。蛋白质组图谱的人，在电子基因组分析，遗传(shRNA和CRISPR/Cas9)和药物策略，以及一个体外人体临床前模型。我们发现WNK1在卵巢癌中是一种高度磷酸化的蛋白，发现它的激活或高表达对患者的生存有负面影响。基因组分析显示WNK1在人卵巢肿瘤中扩增。从机制上，我们证明了WNK1在卵巢癌中通过MEK5-ERK5信号模块发挥作用。功能丧失，遗传学或药理学实验表明，靶向WNK1-MEK5-ERK5途径具有抗增殖和抗肿瘤作用。更多的研究表明，这一途径调节了MEK1/2抑制剂曲美替尼的抗肿瘤特性。因此，曲美替尼的治疗激活了WNK1-MEK5-ERK5途径，增加了这种作用可能限制ERK1/2靶向治疗卵巢癌的益处。此外，在不同的实验环境中，包括卵巢癌细胞与自体患者血清培养的体外患者来源模型，我们显示抑制WNK1或MEK5增加了曲美替尼的抗增殖和抗肿瘤效果。本研究揭示了WNK1-MEK5-ERK5轴参与卵巢癌的病理生理学，开启了作用于这一途径的治疗目的的可能性。本研究的另一个重要发现是曲美替尼激活了信号轴，绕过了这种药物的抗肿瘤效果。这一事实应该在曲美替尼用于卵巢癌的背景下考虑。WNK1的激活与卵巢癌患者的预后更差相关。WNK1通过ERK5信号通路传递细胞增殖信号。曲美替尼可激活WNK1-ERK5通路。曲美替尼联合ERK5途径抑制剂可能会改善患者的预后。
The dismal prognosis of advanced ovarian cancer calls for the development of novel therapies to improve disease outcome. In this regard, we set out to discover new molecular entities and to assess the preclinical effectiveness of their targeting. Cell lines, mice and human ovarian cancer samples were used. Proteome profiling of human phosphokinases, in silico genomic analyses, genetic (shRNA and CRISPR/Cas9) and pharmacological strategies as well as an ex vivo human preclinical model were performed. We identified WNK1 as a highly phosphorylated protein in ovarian cancer and found that its activation or high expression had a negative impact on patients’ survival. Genomic analyses showed amplification of WNK1 in human ovarian tumours. Mechanistically, we demonstrate that WNK1 exerted its action through the MEK5–ERK5 signalling module in ovarian cancer. Loss of function, genetic or pharmacological experiments, demonstrated anti‐proliferative and anti‐tumoural effects of the targeting of the WNK1–MEK5–ERK5 route. Additional studies showed that this pathway modulated the anti‐tumoural properties of the MEK1/2 inhibitor trametinib. Thus, treatment with trametinib activated the WNK1–MEK5–ERK5 route, raising the possibility that this effect may limit the therapeutic benefit of ERK1/2 targeting in ovarian cancer. Moreover, in different experimental settings, including an ex vivo patient‐derived model consisting of ovarian cancer cells cultured with autologous patient sera, we show that inhibition of WNK1 or MEK5 increased the anti‐proliferative and anti‐tumour efficacy of trametinib. The present study uncovers the participation of WNK1–MEK5–ERK5 axis in ovarian cancer pathophysiology, opening the possibility of acting on this pathway with therapeutic purposes. Another important finding of the present study was the activation of that signalling axis by trametinib, bypassing the anti‐tumoural efficacy of this drug. That fact should be considered in the context of the use of trametinib in ovarian cancer. Activation of WNK1 associates to a worse ovarian cancer patient outcome. WNK1 signals cell proliferation through the ERK5 pathway. Trametinib provokes activation of the WNK1–ERK5 pathway. Combining trametinib with ERK5 route inhibitors may improve patients’ outcome.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
16.6
作者：
de Jong PR;Taniguchi K;Harris AR;Bertin S;Takahashi N;Duong J;Campos AD;Powis G;Corr M;Karin M;Raz E
通讯作者：
Raz E
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
DOI：
10.1016/s0140-6736(21)02175-9
发表时间：
2022-02-05
期刊：
Lancet (London, England)
影响因子：
--
作者：
Gershenson DM;Miller A;Brady WE;Paul J;Carty K;Rodgers W;Millan D;Coleman RL;Moore KN;Banerjee S;Connolly K;Secord AA;O'Malley DM;Dorigo O;Gaillard S;Gabra H;Slomovitz B;Hanjani P;Farley J;Churchman M;Ewing A;Hollis RL;Herrington CS;Huang HQ;Wenzel L;Gourley C
通讯作者：
Gourley C
影响因子：
158.5
作者：
Burger, Robert A.;Brady, Mark F.;Liang, Sharon X.
通讯作者：
Liang, Sharon X.