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, researchers from the CRCINA and INSERM, Université d’Angers & Université de Nantes in Nantes, and from the Laboratories Jacques Louis Lions at Paris, together with MOLAB researchers 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). They observed that 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. Thus, the work identified a population with tolerant-like features in glioblastoma, which could constitute a therapeutic target.
"Identification of a transient state during the acquisition of temozolomide resistance in glioblastoma"
Marion Rabé, Solenne Dumont, Arturo Álvarez-Arenas, Hicham Janati, Juan Belmonte-Beitia, Gabriel F. Calvo, Christelle Thibault-Carpentier, Quentin Séry, Cynthia Chauvin, Noémie Joalland, Floriane Briand, Stéphanie Blandin, Emmanuel Scotet, Claire Pecqueur, Jean Clairambault, Lisa Oliver, Victor Perez-Garcia, Arulraj Nadaradjane, Pierre-François Cartron, Catherine Gratas & François M. Vallette
Cell Death & Disease volume 11, Article number: 19 (2020)