Data from A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma
Year: 2023
Type: other
Abstract: Purpose: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy. Experimental Design: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts. Results: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy. Conclusions: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.
Authors: Sied Kebir, Vivien Ullrich, Pia Berger, Celia Dobersalske, Sarah Langer, Laurèl Rauschenbach, Daniel Trageser, Andreas Till, Franziska K. Lorbeer, Anja Wieland, Timo Wilhelm-Buchstab, Ashar Ahmad, Holger Fröhlich, Igor Cima, Shruthi Prasad, Johann Matschke, Verena Jendrossek, Marc Remke, Barbara M. Grüner, Alexander Roesch, Jens T. Siveke, Christel Herold-Mende, Tobias Blau, Kathy Keyvani, Frank K.H. van Landeghem, Torsten Pietsch, Jörg Felsberg, Guido Reifenberger, Michael Weller, Ulrich Sure, Oliver Brüstle, Matthias Simon, Martin Glas, Björn Scheffler
Institutions: German Cancer Research Center, Essen University Hospital, Deutsches Konsortium für Translationale Krebsforschung, University of Bonn, University Hospital Bonn, Life & Brain (Germany), Bonn Aachen International Center for Information Technology, Fraunhofer Institute for Algorithms and Scientific Computing, Düsseldorf University Hospital, Heidelberg University, University of Duisburg-Essen, Heinrich Heine University Düsseldorf, University of Zurich, University Hospital Zurich, Bielefeld University
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Awards: G1613339307, G2785209683, G2897501204, G2958871262, G30797394, G322982942, G3365666211, G3873772630, G4607898173, Zielgerichtete Therapie von klonalexpandierenden Tumorzellen im Rezidiv des Glioblastoms – 2. Förderphase: CoKlinische Studien zur epigenetisch bedingten Resistenz, G8482385449, KFO 337: Phänotypische Therapie und Immunresistenz in Krebs (PhenoTImE): Präklinischer und translationaler Fortschritt der KFO 337
OpenAlex ID: W4361958919