GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant
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 Shaw, Marta Pérez‐Somarriba, Sara Temelso, Florence I. Raynaud, Ruth Ruddle, Eshini Panditharatna, Bernhard Englinger, Hafsa M. Mire, Jiang Li, Andrezza Nascimento, Jenna LaBelle, Rebecca Haase, Jacob S Rozowsky, Sina Neyazi, Alicia-Christina Baumgartner, Sophia Castellani, Samantha E. Hoffman, Amy Cameron, Murry Morrow, Quang‐Dé 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 Sundström, Rebecca D. Hodge, Ed S. Lein, Sameer Agnihotri, David D. Eisenstat, Simon Stapleton, Andrew King, Cristina Bleil, Angela Mastronuzzi, Kristina A. Cole, Angela J. Waanders, Ángel M. Carcaboso, Ulrich Schüller, Darren Hargrave, Maria Vinci, Fernando Carceller, Christine Haberler, Irene Slavc, Sten Linnarsson, Johannes Gojo, Michelle Monje, Chris Jones, Mariella G. Filbin
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.