ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma.
ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma.
复制标题
DOI：
10.1038/s41388-022-02251-8
复制
发表时间：
2022-04
期刊：
影响因子：
8
通讯作者：
Pardo, Olivier E.
中科院分区：
文献类型：
--
作者：
Georgiou, Marina;Ntavelou, Panagiota;Stokes, William;Roy, Rajat;Maher, Geoffrey J.;Stoilova, Tsvetana;Rakhit, Callum P.;Martins, Miguel;Ajuh, Paul;Horowitz, Neil;Berkowitz, Ross S.;Elias, Kevin;Seckl, Michael J.;Pardo, Olivier E.
低风险妊娠滋养细胞肿瘤包括绒毛膜癌通常有效地治疗甲氨蝶呤（MTX）作为一线治疗。然而，MTX耐药（MTX-R）发生在至少约33%的病例中。这有时可以用放线菌素D挽救，但通常需要毒性更大的联合化疗。此外，可能需要额外的治疗，对于高风险患者，5%的人仍然死于多药耐药疾病。因此，需要毒性较小并可以逆转MTX-R的新治疗方法。在这里，我们比较了蛋白质组/磷酸化蛋白质组的MTX耐药和敏感绒毛膜癌细胞使用定量质谱法，以确定治疗上可行的分子变化与MTX-R。蛋白质组数据的生物信息学分析确定细胞周期和DNA损伤修复为与MTX-R相关的主要途径。MTX-R绒毛膜癌细胞在G1期经历细胞周期延迟，这使得它们能够以ATR依赖性方式通过非同源末端连接更有效地修复DNA损伤。细胞周期蛋白依赖性激酶4（CDK 4）表达增加和p16 Ink 4a在耐药细胞中的丢失表明，CDK 4抑制可能是治疗MTX-R绒毛膜癌的策略。事实上，使用遗传沉默或临床相关抑制剂Palbociclib抑制CDK 4/6在体外和原位体内小鼠模型中都诱导了生长抑制。最后，靶向ATR途径，遗传或非遗传地，在体外使耐药性细胞对MTX重新敏感，并有效地防止体内MTX-R肿瘤的生长。简而言之，我们确定了两种新的治疗策略来解决MTX-R绒毛膜癌，可以迅速转化为临床。
Low-risk gestational trophoblastic neoplasia including choriocarcinoma is often effectively treated with Methotrexate (MTX) as a first line therapy. However, MTX resistance (MTX-R) occurs in at least ≈33% of cases. This can sometimes be salvaged with actinomycin-D but often requires more toxic combination chemotherapy. Moreover, additional therapy may be needed and, for high-risk patients, 5% still die from the multidrug-resistant disease. Consequently, new treatments that are less toxic and could reverse MTX-R are needed. Here, we compared the proteome/phosphoproteome of MTX-resistant and sensitive choriocarcinoma cells using quantitative mass-spectrometry to identify therapeutically actionable molecular changes associated with MTX-R. Bioinformatics analysis of the proteomic data identified cell cycle and DNA damage repair as major pathways associated with MTX-R. MTX-R choriocarcinoma cells undergo cell cycle delay in G1 phase that enables them to repair DNA damage more efficiently through non-homologous end joining in an ATR-dependent manner. Increased expression of cyclin-dependent kinase 4 (CDK4) and loss of p16Ink4a in resistant cells suggested that CDK4 inhibition may be a strategy to treat MTX-R choriocarcinoma. Indeed, inhibition of CDK4/6 using genetic silencing or the clinically relevant inhibitor, Palbociclib, induced growth inhibition both in vitro and in an orthotopic in vivo mouse model. Finally, targeting the ATR pathway, genetically or pharmacologically, re-sensitised resistant cells to MTX in vitro and potently prevented the growth of MTX-R tumours in vivo. In short, we identified two novel therapeutic strategies to tackle MTX-R choriocarcinoma that could rapidly be translated into the clinic.
登录
查看更多内容
ATR在线粒体上扮演直接的抗凋亡作用，该抗凋亡作用受Prolyl异构酶PIN1的调节。
影响因子：
16
作者：
Hilton BA;Li Z;Musich PR;Wang H;Cartwright BM;Serrano M;Zhou XZ;Lu KP;Zou Y
通讯作者：
Zou Y
影响因子：
4.7
作者：
Bolze, Pierre-Adrien;Lopez, Jonathan;Mallet, Francois
通讯作者：
Mallet, Francois
影响因子：
3.9
作者：
Araki, Takako;Liu, Ning-Ai;Melmed, Shlomo
通讯作者：
Melmed, Shlomo
影响因子：
2.1
作者：
Bertino, Joseph R.
通讯作者：
Bertino, Joseph R.
影响因子：
3.6
作者：
Hochhaus, Andreas;Erben, Philipp;Mueller, Martin C.
通讯作者：
Mueller, Martin C.