6D5Y

Crystal structure of ERK2 G169D mutant

6D5Y の概要

• エントリーDOI: 10.2210/pdb6d5y/pdb
• 分子名称: Mitogen-activated protein kinase 1 (1 entity in total)
• 機能のキーワード: transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40533.63

構造登録者

Yin, J.,Jaiswal, B.S.,Wang, W. (登録日: 2018-04-19, 公開日: 2019-02-27, 最終更新日: 2024-03-13)

主引用文献

Jaiswal, B.S.,Durinck, S.,Stawiski, E.W.,Yin, J.,Wang, W.,Lin, E.,Moffat, J.,Martin, S.E.,Modrusan, Z.,Seshagiri, S.
ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy.
Clin. Cancer Res., 24:4044-4055, 2018

PubMed Abstract: MAPK pathway inhibitors targeting BRAF and MEK have shown clinical efficacy in patients with RAF- and/or RAS-mutated tumors. However, acquired resistance to these agents has been an impediment to improved long-term survival in the clinic. In such cases, targeting ERK downstream of BRAF/MEK has been proposed as a potential strategy for overcoming acquired resistance. Preclinical studies suggest that ERK inhibitors are effective at inhibiting BRAF/RAS-mutated tumor growth and overcome BRAF or/and MEK inhibitor resistance. However, as observed with other MAPK pathway inhibitors, treatment with ERK inhibitors is likely to cause resistance in the clinic. Here, we aimed to model the mechanism of resistance to ERK inhibitors. We tested five structurally different ATP-competitive ERK inhibitors representing three different scaffolds on BRAF/RAS-mutant cancer cell lines of different tissue types to generate resistant lines. We have used modeling, structural biology, and genomic analysis to understand the development of resistance to ERK inhibitors and the mechanisms leading to it. We have identified mutations in ERK1/2, amplification and overexpression of ERK2, and overexpression of EGFR/ERBB2 as mechanisms of acquired resistance. Structural analysis of ERK showed that specific compounds that induced on-target ERK mutations were impaired in their ability to bind mutant ERK. We show that in addition to MEK inhibitors, ERBB receptor and PI3K/mTOR pathway inhibitors are effective in overcoming ERK-inhibitor resistance. These findings suggest that combination therapy with MEK or ERBB receptor or PI3K/mTOR and ERK inhibitors may be an effective strategy for managing the emergence of resistance in the clinic. .

PubMed: 29760222
DOI: 10.1158/1078-0432.CCR-17-3674

実験手法

X-RAY DIFFRACTION (2.86 Å)