当前位置: X-MOL 学术Drug Resist. Updat. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
TAK-ing aim at chemoresistance: The emerging role of MAP3K7 as a target for cancer therapy
Drug Resistance Updates ( IF 24.3 ) Pub Date : 2017-11-03 , DOI: 10.1016/j.drup.2017.10.004
Raffaela Santoro , Carmine Carbone , Geny Piro , Paul J. Chiao , Davide Melisi

Cellular drug resistance remains the main obstacle to the clinical efficacy of cancer chemotherapy. Alterations in key pathways regulating cell cycle checkpoints, apoptosis and Epithelial to Mesenchymal Transition (EMT), such as the Mitogen-activated protein kinase (MAPK) pathway, appear to be closely associated to cancer chemoresistance.

Transforming growth factor-β (TGF-β)- activated kinase 1 (TAK1, also known as MAP3K7) is a serine/threonine kinase in the mitogen-activated protein kinase (MAP3K) family. It represents the cellular hub to which IL1, TGF-β and Wnt signaling pathways converge. By regulating the phosphorylation status and activities of transcription factors including Activated Protein-1 (AP-1) and nuclear factor κ-B (NF-κB), TAK1 mediates inflammatory and pro-survival responses. The interest towards the therapeutic targeting of TAK1 is due to its identification as one of the main mediators of both chemoresistance and EMT in several types of tumors, and as the possible target for a subset of treatment-refractory colon cancers exhibiting mutated KRAS or activated WNT pathways. For these reasons, many efforts have been made to design inhibitors of TAK1 kinase activity, which could be used to reverse TAK1-mediated chemoresistance. The activity of these inhibitors, in combination with the most commonly used chemotherapeutic drugs, has been tested in preclinical studies, proving the efficacy of TAK1 inhibition in reducing tumor growth and survival following chemotherapy administration. In the first part of this review, we describe the mechanisms underlying TAK1 regulation such as phosphorylation, ubiquitination and targeting by microRNAs. We then focus on the development of therapeutic small molecule inhibitors of TAK1 kinase activity, as well as preclinical studies supporting the role of TAK1 as a potential target for enhancing the response of tumors to anticancer therapies.



中文翻译:

TAK- ing致力于化学抗性:MAP3K7作为癌症治疗靶标的新兴作用

细胞耐药性仍然是癌症化学疗法临床疗效的主要障碍。调节细胞周期检查点,细胞凋亡和上皮向间质转化(EMT)的关键途径的改变,例如促分裂原激活的蛋白激酶(MAPK)途径,似乎与癌症的化学抗性密切相关。

转化生长因子-β(TGF-β)激活的激酶1(TAK1,也称为MAP3K7)是丝裂原激活的蛋白激酶(MAP3K)家族中的丝氨酸/苏氨酸激酶。它代表了IL1,TGF-β和Wnt信号通路向其汇合的细胞中心。通过调节磷酸化状态和转录因子(包括活化蛋白1(AP-1)和核因子κ-B(NF-κB))的活性,TAK1介导炎症反应和存活前反应。对TAK1靶向治疗的兴趣是由于它被确定为几种类型肿瘤中化学抗药性和EMT的主要介体之一,并且可能是治疗性难治性结肠癌亚型的可能靶标,这些结肠癌表现出KRAS突变或WNT活化途径。由于这些原因,为设计TAK1激酶活性抑制剂做出了许多努力,可以用来逆转TAK1介导的化学抗性。在临床前研究中已经测试了这些抑制剂与最常用的化疗药物联合使用的活性,证明了TAK1抑制作用在化疗后降低肿瘤生长和存活方面的功效。在这篇综述的第一部分中,我们描述了TAK1调控的基础机制,如磷酸化,泛素化和microRNA靶向。然后,我们专注于开发TAK1激酶活性的治疗性小分子抑制剂,以及支持TAK1作为增强肿瘤对抗癌治疗反应的潜在靶标作用的临床前研究。在临床前研究中已经对与最常用的化疗药物合用的药物进行了试验,证明了TAK1抑制在化疗后降低肿瘤生长和存活方面的功效。在这篇综述的第一部分中,我们描述了TAK1调控的基础机制,如磷酸化,泛素化和microRNA靶向。然后,我们专注于开发TAK1激酶活性的治疗性小分子抑制剂,以及支持TAK1作为增强肿瘤对抗癌治疗反应的潜在靶标作用的临床前研究。在临床前研究中已经对与最常用的化疗药物合用的药物进行了试验,证明了TAK1抑制在化疗后降低肿瘤生长和存活方面的功效。在这篇综述的第一部分中,我们描述了TAK1调控的基础机制,例如磷酸化,泛素化和microRNA靶向。然后,我们专注于开发TAK1激酶活性的治疗性小分子抑制剂,以及支持TAK1作为增强肿瘤对抗癌治疗反应的潜在靶标作用的临床前研究。我们描述了TAK1调控的基础机制,例如磷酸化,泛素化和microRNA靶向。然后,我们专注于开发TAK1激酶活性的治疗性小分子抑制剂,以及支持TAK1作为增强肿瘤对抗癌治疗反应的潜在靶标作用的临床前研究。我们描述了TAK1调控的基础机制,例如磷酸化,泛素化和microRNA靶向。然后,我们专注于开发TAK1激酶活性的治疗性小分子抑制剂,以及支持TAK1作为增强肿瘤对抗癌治疗反应的潜在靶标作用的临床前研究。

更新日期:2017-11-03
down
wechat
bug