美国博德研究所Mariella G. Filbin等研究人员合作发现，GABA能神经元谱系发育决定弥漫性半球型胶质瘤H3G34突变体中的可临床干预靶点。该项研究成果发表在2024年9月9日出版的《癌细胞》杂志上。

研究人员揭示了中间神经元谱系发育连续过程中的细胞层次结构，发现弥漫性半球型胶质瘤H3G34R/V突变体（DHG-H3G34）与人脑发育过程中围绕中间神经元巢的前体细胞流的空间模式相似。结合全基因组CRISPR-Cas9筛选结果，研究人员确定了在中间神经元谱系前体细胞中上调的基因是主要的依赖性因素。

其中，CDK6被确定为可靶向的脆弱点：DHG-H3G34肿瘤细胞对CDK4/6抑制剂和CDK6特异性降解剂表现出增强的敏感性，促进其向更成熟的中间神经元样状态转变，减少肿瘤生长，并延长了异种移植模型的生存期。

值得注意的是，一名患有进展性DHG-H3G34的患者在接受CDK4/6抑制剂治疗后获得了17个月的病情稳定。该研究强调了组织在特定区域内的中间神经元前体样状态作为DHG-H3G34的显著脆弱点，并突出了CDK6作为潜在临床可干预靶点的前景。

据介绍，DHG-H3G34是致命的脑肿瘤，缺乏针对性的治疗方法。尽管其起源于中间神经元前体细胞，但利用这一起源进行治疗探索尚未展开。

附：英文原文

Title: GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant

Author: Ilon Liu, Gustavo Alencastro Veiga Cruzeiro, Lynn Bjerke, Rebecca F. Rogers, Yura Grabovska, Alexander Beck, Alan Mackay, Tara Barron, Olivia A. Hack, Michael A. Quezada, Valeria Molinari, McKenzie L. Shaw, Marta Perez-Somarriba, Sara Temelso, Florence Raynaud, Ruth Ruddle, Eshini Panditharatna, Bernhard Englinger, Hafsa M. Mire, Li Jiang, Andrezza Nascimento, Jenna LaBelle, Rebecca Haase, Jacob Rozowsky, Sina Neyazi, Alicia-Christina Baumgartner, Sophia Castellani, Samantha E. Hoffman, Amy Cameron, Murry Morrow, Quang-De Nguyen, Giulia Pericoli, Sibylle Madlener, Lisa Mayr, Christian Dorfer, Rene Geyeregger, Christopher Rota, Gerda Ricken, Keith L. Ligon, Sanda Alexandrescu, Rodrigo T. Cartaxo, Benison Lau, Santhosh Uphadhyaya, Carl Koschmann, Emelie Braun, Miri Danan-Gotthold, Lijuan Hu, Kimberly Siletti, Erik Sundstrm, Rebecca Hodge, Ed Lein, Sameer Agnihotri, David D. Eisenstat, Simon Stapleton, Andrew King, Cristina Bleil, Angela Mastronuzzi, Kristina A. Cole, Angela J. Waanders, Angel Montero Carcaboso, Ulrich Schüller, Darren Hargrave, Maria Vinci, Fernando Carceller

Issue&Volume: 2024/09/09

Abstract: Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.

DOI: 10.1016/j.ccell.2024.08.006

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00305-2