小柯机器人

MEN1突变介导对menin抑制的临床耐药性
2023-03-23 11:41

美国纪念斯隆凯特琳癌症中心Sheng F. Cai,Ross L. Levine和美国波士顿儿童医院和哈佛医学院Scott A. Armstrong共同合作,近期取得重要工作进展。他们研究发现,MEN1突变介导对menin抑制的临床耐药性。相关研究成果于2023年3月15日在线发表于《自然》杂志上。

据介绍,染色质结合蛋白是造血细胞状态的关键调节因子。由混合谱系白血病1基因(KMT2Ar)重排或核仁磷酸蛋白基因突变(NPM1)驱动的急性白血病需要由MEN1基因编码的染色质衔接蛋白menin来维持异常的白血病基因表达程序。在第一阶段人体临床试验中,旨在破坏 menin-MLL1 相互作用的menin抑制剂revumenib在患有KMT2Ar或突变的NPM1的白血病患者中诱导了临床反应。

研究人员发现,在对menin抑制获得性耐药的患者中,在revumenib-menin界面发现了MEN1的体细胞突变。与患者的遗传数据一致,在异种移植物模型和无偏见的碱基编辑器筛选中,抑制剂-menin界面突变代表了治疗耐药性的保守机制。这些突变体通过产生影响小分子结合但不影响与天然配体MLL1相互作用的结构扰动来减弱药物-靶标结合,并防止抑制剂诱导的menin和MLL1从染色质中排出。

总之,研究人员表明,这项研究首次证明了染色质靶向治疗药物对患者施加足够的选择压力,以推动导致染色质持续占据的逃逸突变体的演化,这表明了常见的治疗耐药性的共同机制。

附:英文原文

Title: MEN1 mutations mediate clinical resistance to menin inhibition

Author: Perner, Florian, Stein, Eytan M., Wenge, Daniela V., Singh, Sukrit, Kim, Jeonghyeon, Apazidis, Athina, Rahnamoun, Homa, Anand, Disha, Marinaccio, Christian, Hatton, Charlie, Wen, Yanhe, Stone, Richard M., Schaller, David, Mowla, Shoron, Xiao, Wenbin, Gamlen, Holly A., Stonestrom, Aaron J., Persaud, Sonali, Ener, Elizabeth, Cutler, Jevon A., Doench, John G., McGeehan, Gerard M., Volkamer, Andrea, Chodera, John D., Nowak, Radosaw P., Fischer, Eric S., Levine, Ross L., Armstrong, Scott A., Cai, Sheng F.

Issue&Volume: 2023-03-15

Abstract: Chromatin-binding proteins are critical regulators of cell state in haematopoiesis1,2. Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs3,4,5. In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin–MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref. 6). Here we identified somatic mutations in MEN1 at the revumenib–menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor–menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug–target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance.

DOI: 10.1038/s41586-023-05755-9

Source: https://www.nature.com/articles/s41586-023-05755-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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