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.

中文翻译：

---

鉴定胶质母细胞瘤中替莫唑胺耐药性获得过程中的瞬时状态。

耐药性限制了癌症的治疗效果，并通过不明确的机制导致肿瘤复发。胶质母细胞瘤（GBM）是成人中最致命的脑瘤。GBM在诊断时或治疗后对标准化疗替莫唑胺（TMZ）耐药。为了更好地了解这种抗药性的获得，我们使用数学模型，RNA测序，单细胞分析，人胶质瘤细胞系（U251）的功能和药物分析相结合进行了纵向研究。在以细胞死亡诱导为特征的初始反应后，细胞进入由缓慢生长，独特形态和新陈代谢转变所定义的瞬时状态。与该种群相关的特定基因表达揭示了染色质重塑。实际上，组蛋白脱乙酰基酶抑制剂曲古抑素（TSA）特别消除了该种群，从而阻止了快速生长的TMZ耐药细胞的出现。总之，我们已经在胶质母细胞瘤中鉴定了具有耐受性特征的人群，可以构成治疗靶标。