A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma

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. To identify candidate ma...

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Bibliographic Details
Published in:Clinical cancer research 2023-01, Vol.29 (2), p.488-500
Main Authors: Kebir, Sied, Ullrich, Vivien, Berger, Pia, Dobersalske, Celia, Langer, Sarah, Rauschenbach, Laurèl, Trageser, Daniel, Till, Andreas, Lorbeer, Franziska K, Wieland, Anja, Wilhelm-Buchstab, Timo, Ahmad, Ashar, Fröhlich, Holger, Cima, Igor, Prasad, Shruthi, Matschke, Johann, Jendrossek, Verena, Remke, Marc, Grüner, Barbara M, Roesch, Alexander, Siveke, Jens T, Herold-Mende, Christel, Blau, Tobias, Keyvani, Kathy, van Landeghem, Frank K H, Pietsch, Torsten, Felsberg, Jörg, Reifenberger, Guido, Weller, Michael, Sure, Ulrich, Brüstle, Oliver, Simon, Matthias, Glas, Martin, Scheffler, Björn
Format: Article
Language:English
Subjects:
Antineoplastic Agents, Alkylating - pharmacology
Antineoplastic Agents, Alkylating - therapeutic use
Brain Neoplasms - drug therapy
Brain Neoplasms - genetics
Brain Neoplasms - pathology
Cell Line, Tumor
Drug Resistance, Neoplasm - genetics
Glioblastoma - drug therapy
Glioblastoma - genetics
Glioblastoma - pathology
Humans
Proto-Oncogene Proteins c-akt
Temozolomide
Translational Cancer Mechanisms and Therapy
Xenograft Model Antitumor Assays
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Summary: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. 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. 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. 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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-22-0611