ERK5 Signalling and Resistance to ERK1/2 Pathway Therapeutics: The Path Less Travelled?
ERK5 Signalling and Resistance to ERK1/2 Pathway Therapeutics: The Path Less Travelled?
复制标题
ERK5信号通路与ERK1/2耐药途径治疗：一条较少被采用的途径？
DOI：
10.3389/fcell.2022.839997
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发表时间：
2022
影响因子：
5.5
通讯作者：
Lochhead PA
中科院分区：
文献类型：
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作者：
Cook SJ;Lochhead PA
RAS调节的RAF-MEK 1/2-ERK 1/2信号通路在人类癌症中经常失调。黑色素瘤尤其表现出高发生率的激活BRAFV 600 E/K和NRASQ 61 L/K突变，并且这些细胞对这些突变癌蛋白的活性上瘾。因此，三种不同的BRAF抑制剂（BRAFi）现已被批准用于BRAFV 600 E/K突变型黑色素瘤，并改变了这种疾病的治疗。尽管如此，临床反应通常是短暂的，因为肿瘤细胞产生耐药性。这些耐药机制通常涉及ERK 1/2信号传导的恢复，BRAFi现在与三种批准的MEK 1/2抑制剂（MEKi）之一联合使用，以提供更持久但仍然短暂的临床反应。此外，还开发了ERK 1/2（ERK 1/2 i）抑制剂以抵消ERK 1/2信号传导。然而，最近的研究表明，BRAFi/MEKi和ERK 1/2 i抗性可以通过激活导致ERK 5激活的平行信号传导途径而产生，ERK 5是一种不寻常的蛋白激酶，包含激酶结构域和转录反式激活结构域。在这里，我们回顾了支持ERK 5作为BRAFi/MEKi和ERK 1/2 i抗性的介导剂的证据。我们还回顾了小分子靶向ERK 5信号传导的挑战，包括转录反式激活结构域的矛盾激活，并讨论了可用于靶向ERK 5的新的治疗方式。
The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is frequently de-regulated in human cancer. Melanoma in particular exhibits a high incidence of activating BRAFV600E/K and NRASQ61L/K mutations and such cells are addicted to the activity of these mutant oncoproteins. As a result three different BRAF inhibitors (BRAFi) have now been approved for BRAFV600E/K- mutant melanoma and have transformed the treatment of this disease. Despite this, clinical responses are typically transient as tumour cells develop resistance. These resistance mechanisms frequently involve reinstatement of ERK1/2 signalling and BRAFi are now deployed in combination with one of three approved MEK1/2 inhibitors (MEKi) to provide more durable, but still transient, clinical responses. Furthermore, inhibitors to ERK1/2 (ERK1/2i) have also been developed to counteract ERK1/2 signalling. However, recent studies have suggested that BRAFi/MEKi and ERK1/2i resistance can arise through activation of a parallel signalling pathway leading to activation of ERK5, an unusual protein kinase that contains both a kinase domain and a transcriptional transactivation domain. Here we review the evidence supporting ERK5 as a mediator of BRAFi/MEKi and ERK1/2i resistance. We also review the challenges in targeting ERK5 signalling with small molecules, including paradoxical activation of the transcriptional transactivation domain, and discuss new therapeutic modalities that could be employed to target ERK5.
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DOI：
10.1073/pnas.1707929115
发表时间：
2018-03-20
影响因子：
11.1
作者：
Giurisato E;Xu Q;Lonardi S;Telfer B;Russo I;Pearson A;Finegan KG;Wang W;Wang J;Gray NS;Vermi W;Xia Z;Tournier C
通讯作者：
Tournier C
影响因子：
11.2
作者：
Giurisato E;Lonardi S;Telfer B;Lussoso S;Risa-Ebrí B;Zhang J;Russo I;Wang J;Santucci A;Finegan KG;Gray NS;Vermi W;Tournier C
通讯作者：
Tournier C
影响因子：
9.7
作者：
Hoang VT;Yan TJ;Cavanaugh JE;Flaherty PT;Beckman BS;Burow ME
通讯作者：
Burow ME
影响因子：
51.1
作者：
Dummer, Reinhard;Schadendorf, Dirk;Flaherty, Keith
通讯作者：
Flaherty, Keith
影响因子：
64.8
作者：
通讯作者：
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