Dataset Information

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

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.

SUBMITTER: Kebir S

PROVIDER: S-EPMC9843437 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Kebir Sied S Ullrich Vivien V Berger Pia P Dobersalske Celia C Langer Sarah S Rauschenbach Laurèl L Trageser Daniel D Till Andreas A Lorbeer Franziska K FK Wieland Anja A Wilhelm-Buchstab Timo T Ahmad Ashar A Fröhlich Holger H Cima Igor I Prasad Shruthi S Matschke Johann J Jendrossek Verena V Remke Marc M Grüner Barbara M BM Roesch Alexander A Siveke Jens T JT Herold-Mende Christel C Blau Tobias T Keyvani Kathy K van Landeghem Frank K H FKH Pietsch Torsten T Felsberg Jörg J Reifenberger Guido G Weller Michael M Sure Ulrich U Brüstle Oliver O Simon Matthias M Glas Martin M Scheffler Björn B

Clinical cancer research : an official journal of the American Association for Cancer Research 20230101 2

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 ...[more]

PMID: 36239995

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Project description:BackgroundGlioblastoma (GBM) is a highly aggressive brain tumor characterized by poor prognosis and limited therapeutic options. Understanding the molecular mechanisms driving GBM progression is essential for developing more effective diagnostic and therapeutic approaches. Specifically, investigating Cell Division Cycle-Associated (CDCA) genes offers new perspectives on cell cycle regulation and the proliferation of GBM cells, which are key factors in tumor growth and resistance to treatment. These genes have not been extensively studied in GBM, making them a promising area for targeted research and potential therapeutic interventions. This project was launched to elucidate the pathogenic, diagnostic, and therapeutic roles of CDCA genes in GBM.MethodologyTotal RNA was extracted from GBM cell lines followed by RT-qPCR to analyze the expression of CDCA genes. The expression validation, prognostic significance, and mutational analysis of CDCA genes were performed using various databases. Functional assays, including gene knockdown, colony formation, proliferation, and wound healing, were conducted in U87MG cells to assess the role of CDCA7 and CDCA8 in GBM.ResultsThe expression analysis of CDCA genes in 12 GBM cell lines and 6 normal brain cell lines revealed significant overexpression of these genes in GBM. ROC curve analysis demonstrated excellent diagnostic potential, with AUC values of 1 for most genes. This indicates that CDCA gene expression effectively distinguishes GBM cells from normal brain cells. Validation using additional TCGA data confirmed the upregulation of these genes in GBM tumors, with significant association to key cancer-related pathways. Survival analysis showed that higher expression of CDCA genes correlated with poor prognosis in GBM patients. Mutation, CNV, and methylation analyses revealed alterations in these genes, further supporting their role in GBM. Additionally, CDCA gene expression was linked to immune modulation and cell cycle-related functions, suggesting their involvement in immune evasion and tumor proliferation. Knockdown experiments of CDCA7 and CDCA8 in U87MG cells demonstrated a reduction in cell proliferation, colony formation, and migration, highlighting their potential as therapeutic targets.ConclusionOverall, our findings suggest that CDCA genes could serve as both diagnostic biomarkers and therapeutic targets for GBM.

Project description:Breaking resistance to chemotherapy is a major goal of combination therapy in many tumors, including advanced neuroblastoma. We recently demonstrated that increased activity of the PI3K/Akt network is associated with poor prognosis, thus providing an ideal target for chemosensitization. Here we show that targeted therapy using the PI3K/mTOR inhibitor NVP-BEZ235 significantly enhances doxorubicin-induced apoptosis in neuroblastoma cells. Importantly, this increase in apoptosis was dependent on scheduling: while pretreatment with the inhibitor reduced doxorubicin-induced apoptosis, the sensitizing effect in co-treatment could further be increased by delayed addition of the inhibitor post chemotherapy. Desensitization for doxorubicin-induced apoptosis seemed to be mediated by a combination of cell cycle-arrest and autophagy induction, whereas sensitization was found to occur at the level of mitochondria within one hour of NVP-BEZ235 posttreatment, leading to a rapid loss of mitochondrial membrane potential with subsequent cytochrome c release and caspase-3 activation. Within the relevant time span we observed marked alterations in a ∼30 kDa protein associated with mitochondrial proteins and identified it as VDAC1/Porin protein, an integral part of the mitochondrial permeability transition pore complex. VDAC1 is negatively regulated by the PI3K/Akt pathway via GSK3β and inhibition of GSK3β, which is activated when Akt is blocked, ablated the sensitizing effect of NVP-BEZ235 posttreatment. Our findings show that cancer cells can be sensitized for chemotherapy induced cell death - at least in part - by NVP-BEZ235-mediated modulation of VDAC1. More generally, we show data that suggest that sequential dosing, in particular when multiple inhibitors of a single pathway are used in the optimal sequence, has important implications for the general design of combination therapies involving molecular targeted approaches towards the PI3K/Akt/mTOR signaling network.

Dataset Information

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

Purpose

Experimental design

Results

Conclusions

Publications

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

Similar Datasets

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