广谱抑癌基因WEE1研究

Wee1蛋白激酶是丝氨酸/苏氨酸蛋白激酶家族的一员,其主要通过磷酸化细胞分裂周期基因(cell division cycle,Cdc2),下调其活性,进而可以调控细胞G2到M期的转变并调节细胞有丝分裂。
WEE1在染色体浓缩延迟和组蛋白合成中起到关键作用,它在肿瘤发生、发展中具有重要功能。目前已发现很多种WEE1抑制剂,各种WEE1抑制剂与DNA损伤(化疗或放射治疗)相结合的联合治疗方式已取得了很多进展,这些使WEE1成为肿瘤治疗中的一个重要靶点。其中MK-1775是一种有效的，选择性Wee1抑制剂，无细胞试验中IC50为5.2 nM；阻碍G2期DNA损伤检验点。目前处于二期临床中。
Mol Cancer. 2009 Jun 8;8:34. doi: 10.1186/1476-4598-8-34.
Discovery of gene expression-based pharmacodynamic biomarker for a p53 context-specific anti-tumor drug Wee1 inhibitor.
这是PUBMED数据库第一篇关于WEE1激酶的研究文章。文中指出WEE1的细胞周期检查点功能特征，与p53基因存在密切关系。WEE1抑制剂增强肿瘤细胞DNA损失而对正常p53野生细胞无损。
Mol Cancer Ther. 2009 Nov;8(11):2992-3000. doi: 10.1158/1535-7163.MCT-09-0463. Epub 2009 Nov 3.
Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents.
本文指出wee1激酶小分子抑制剂MK-1775有选择性对p53有缺陷的肿瘤细胞具有DNA损失作用。适用于多种恶性肿瘤。
Cancer Biol Ther. 2010 Apr 1;9(7):514-22. Epub 2010 Apr 1.
MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil.
MK-1775增强5FU等DNA损失药物的抗瘤效果。
Clin Cancer Res. 2011 May 1;17(9):2799-806. doi: 10.1158/1078-0432.CCR-10-2580. Epub 2011 Mar 9.
MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts.
MK-1775协同吉西他滨治疗p53缺陷的胰腺癌取得效果。
Mol Cancer Ther. 2011 Dec;10(12):2405-14. doi: 10.1158/1535-7163.MCT-11-0469. Epub 2011 Oct 12.
Targeting radiation-induced G(2) checkpoint activation with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines.
MK-1775协同放疗治疗脑胶质瘤。
Mol Cancer Ther. 2012 Jan;11(1):174-82. doi: 10.1158/1535-7163.MCT-11-0529. Epub 2011 Nov 14.
MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells.
MK-1775治疗骨肉瘤。
Oncogene. 2013 Jun 13;32(24):3001-8. doi: 10.1038/onc.2012.296. Epub 2012 Jul 16.
Forced activation of Cdk1 via wee1 inhibition impairs homologous recombination.
Wee1抑制强力活化CDK1损伤DNA重组。
Cancer Res. 2013 Jan 15;73(2):776-84. doi: 10.1158/0008-5472.CAN-12-2669. Epub 2012 Nov 7.
Combination therapy targeting the Chk1 and Wee1 kinases shows therapeutic efficacy in neuroblastoma.
联合chk1和wee1抑制剂治疗成神经细胞瘤有效果。
Cancer Biol Ther. 2014 Apr;15(4):380-8. doi: 10.4161/cbt.27623. Epub 2014 Jan 14.
Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma.
Wee1抑制剂联合化疗治疗间皮瘤通过阻滞G2/M检查点。
Cancer Res. 2014 May 1;74(9):2510-9. doi: 10.1158/0008-5472.CAN-13-1894. Epub 2014 Mar 13.
WEE1 inhibition alleviates resistance to immune attack of tumor cells undergoing epithelial-mesenchymal transition.
Wee1通过抑制EMT增强对肿瘤免役攻击
Leukemia. 2015 Jan;29(1):27-37. doi: 10.1038/leu.2014.149. Epub 2014 May 5.
Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies.
确定Wee1治疗RAS突变的急性淋巴瘤和其它恶性肿瘤。
Clin Cancer Res. 2014 Oct 1;20(19):5085-96. doi: 10.1158/1078-0432.CCR-14-1038. Epub 2014 Aug 12.
Combined inhibition of Wee1 and PARP1/2 for radiosensitization in pancreatic cancer.
联合wee1和PARP1/2用于放射敏感的胰腺癌
Clin Cancer Res. 2014 Aug 15;20(16):4274-88. doi: 10.1158/1078-0432.CCR-13-2858.
Functional kinomics identifies candidate therapeutic targets in head and neck cancer.
MK-1775治疗头颈部鳞癌
Leukemia. 2015 Apr;29(4):807-18. doi: 10.1038/leu.2014.296. Epub 2014 Oct 6.
A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations.
Wee1抑制剂AZD1775（MK-1775）联合HDAC抑制剂治疗ALL而不管其何种基因突变。
Mol Cancer Ther. 2015 Feb;14(2):608-19. doi: 10.1158/1535-7163.MCT-14-0735-T. Epub 2014 Dec 10.
Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence.
Wee1抑制剂恢复p53突变的头颈部癌顺铂耐药
Clin Cancer Res. 2015 Apr 15;21(8):1916-24. doi: 10.1158/1078-0432.CCR-14-2588. Epub 2015 Jan 21.
The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood-Brain Barrier in Glioblastoma.
MK-1775联合替莫唑安治疗胶质瘤存在血脑屏障的限制
J Clin Oncol. 2015 Oct 20;33(30):3409-15. doi: 10.1200/JCO.2014.60.4009. Epub 2015 May 11.
Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors.
AZD1775一期临床难治的实体瘤。
Clin Cancer Res. 2015 Nov 1;21(21):4831-44. doi: 10.1158/1078-0432.CCR-15-0279. Epub 2015 Jun 29.
Wee-1 Kinase Inhibition Sensitizes High-Risk HPV+ HNSCC to Apoptosis Accompanied by Downregulation of MCl-1 and XIAP Antiapoptotic Proteins.
通过下调MCL-1和XIAP抗凋亡蛋白，Wee1抑制剂AZD-1775对高风险HPV病毒感染的头颈部癌敏感。
Oncotarget. 2015 Sep 29;6(29):28001-10. doi: 10.18632/oncotarget.4830.
AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair.
AZD-1775增强阿胞糖苷治疗T细胞ALL的效果。
Radiat Res. 2015 Dec;184(6):660-9. doi: 10.1667/RR14171.1. Epub 2015 Dec 8.
Targeting of Carbon Ion-Induced G2 Checkpoint Activation in Lung Cancer Cells Using Wee-1 Inhibitor MK-1775.
MK1775阻滞因电离辐射诱导的G2激活治疗肺癌
Int J Radiat Oncol Biol Phys. 2016 Jun 1;95(2):782-90. doi: 10.1016/j.ijrobp.2016.01.028. Epub 2016 Jan 22.
Wee1 Kinase Inhibitor AZD1775 Radiosensitizes Hepatocellular Carcinoma Regardless of TP53 Mutational Status Through Induction of Replication Stress.
AZD-1775治疗肝癌不管是否存在p53突变
Cell Death Dis. 2016 Apr 14;7:e2195. doi: 10.1038/cddis.2016.96.
Wee1 inhibition potentiates Wip1-dependent p53-negative tumor cell death during chemotherapy.
AZD-1775加强化疗导致p53阴性肿瘤细胞死亡。
Oncotarget. 2016 Jun 23. doi: 10.18632/oncotarget.10231. [Epub ahead of print]
Targeting the WEE1 kinase as a molecular targeted therapy for gastric cancer.
AZD-1775治疗胃癌
J Clin Oncol. 2016 Sep 6. pii: JCO675991. [Epub ahead of print]
Phase I Study Evaluating WEE1 Inhibitor AZD1775 As Monotherapy and in Combination With Gemcitabine, Cisplatin, or Carboplatin in Patients With Advanced Solid Tumors.
AZD1775一期临床单药和联合吉西他滨、顺铂、卡铂治疗晚期实体瘤。
Cell Rep. 2016 Sep 13;16(11):3052-61. doi: 10.1016/j.celrep.2016.08.019.
Drosophila Cancer Models Identify Functional Differences between Ret Fusions.
RET融合基因可以联合ret抑制剂和azd1775治疗
Oncotarget. 2016 Sep 28. doi: 10.18632/oncotarget.12311. [Epub ahead of print]
MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells.
本文介绍wee1另一种抑制剂MK-8776