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.
Highlights
Glioblastoma (GBM) is the major and deadliest form of brain cancers in adult
The expression of MGMT is silenced by promoter methylation in approximately half of GBM tumors, and clinical studies have shown that elevated MGMT protein levels or lack of MGMT promoter methylation is associated with TMZ resistance in GBM3,4
We show that histone deacetylase inhibitors (HDI), eliminate this population and prevent resistance to TMZ
Summary
Temozolomide (TMZ) is the standard of care for chemotherapy in patients with GBM. The resistance to this drug is modulated by DNA repair systems and in particular by the expression of O6methylguanine-DNA methyl transferase (MGMT)[1,2]. The evolution of tumor cells under therapy can be viewed as a Darwinian process with replacement of sensitive clones by resistant clones[7] This model is supported by the contention that tumors are composed of a large number of clones and that treatment could change the normal course of cancer evolution as dominant clones at diagnosis could be replaced by others, present within the cell population, because of the selective pressure of therapy[8,9]. The cancer stem cell hypothesis postulates a hierarchical organization of tumors, in which only a proportion of cells is tumorigenic and exhibits intrinsic resistance to most treatments[10]
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