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Identification of a transient state during the acquisition of temozolomide resistance in glioblastoma.

Al's Comment:

 I love this type of research.  They looked at how Temozolomide effects tumor cells over time. We already knew most GBM cells will become resistent to Temozolomide eventually, but they identified a stage that the cells go through where they change to slow growing and change shape.  They identified a drug which interferes with the cell. Sounds like it is worth a try in clinical trials.


Posted on: 01/08/2020

Cell Death Dis. 2020 Jan 6;11(1):19. doi: 10.1038/s41419-019-2200-2.
Identification of a transient state during the acquisition of temozolomide resistance in glioblastoma.
Rabé M1, Dumont S1,2, Álvarez-Arenas A3, Janati H4, Belmonte-Beitia J3, Calvo GF3, Thibault-Carpentier C5, Séry Q1,6, Chauvin C1, Joalland N1, Briand F1, Blandin S7, Scotet E1, Pecqueur C1, Clairambault J4, Oliver L1,8, Perez-Garcia V3, Nadaradjane A1,6, Cartron PF1,6, Gratas C9,10, Vallette FM11,12.
Author information
1
CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France.
2
GenoBiRD, SFR François Bonamy, Université de Nantes, Nantes, France.
3
Department of Mathematics and MôLAB-Mathematical Oncology Laboratory, University of Castilla-la Mancha, Ciudad Real, Spain.
4
Laboratoire Jacques-Louis Lions, Inria, Mamba team and Sorbonne Université, Paris 6, UPMC, Paris, France.
5
IGBMC - CNRS UMR 7104-Inserm U 1258, Université de Strasbourg, 67404, Illkirch, France.
6
Laboratoire de Biologie des Cancers et Théranostic, Institut de Cancérologie de l'Ouest-St Herblain, 44805, Saint-Herblain, France.
7
Plate-Forme MicroPICell, SFR François Bonamy, Université de Nantes, Nantes, France.
8
CHU Nantes, 44093, Nantes, France.
9
CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France. catherine.gratas@univ-nantes.fr.
10
CHU Nantes, 44093, Nantes, France. catherine.gratas@univ-nantes.fr.
11
CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France. francois.vallette@inserm.fr.
12
Laboratoire de Biologie des Cancers et Théranostic, Institut de Cancérologie de l'Ouest-St Herblain, 44805, Saint-Herblain, France. francois.vallette@inserm.fr.
 
Abstract
 
Drug resistance limits the therapeutic efficacy in cancers and leads to tumor recurrence through ill-defined mechanisms. Glioblastoma (GBM) are the deadliest brain tumors in adults. GBM, at diagnosis or after treatment, are resistant to temozolomide (TMZ), the standard chemotherapy. To better understand the acquisition of this resistance, we performed a longitudinal study, using a combination of mathematical models, RNA sequencing, single cell analyses, functional and drug assays in a human glioma cell line (U251). After an initial response characterized by cell death induction, cells entered a transient state defined by slow growth, a distinct morphology and a shift of metabolism. Specific genes expression associated to this population revealed chromatin remodeling. Indeed, the histone deacetylase inhibitor trichostatin (TSA), specifically eliminated this population and thus prevented the appearance of fast growing TMZ-resistant cells. In conclusion, we have identified in glioblastoma a population with tolerant-like features, which could constitute a therapeutic target.
 
PMID: 31907355 DOI: 10.1038/s41419-019-2200-2
 

 


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