DataSheet_1_GBM tumors are heterogeneous in their fatty acid metabolism and modulating fatty acid metabolism sensitizes cancer cells derived from recurring GBM tumors to temozolomide.zip

Glioblastoma is a highly lethal grade of astrocytoma with very low median survival. Despite extensive efforts, there is still a lack of alternatives that might improve these prospects. We uncovered that the chemotherapeutic agent temozolomide impinges on fatty acid synthesis and desaturation in newly diagnosed glioblastoma. This response is, however, blunted in recurring glioblastoma from the same patient. Further, we describe that disrupting cellular fatty acid homeostasis in favor of accumulation of saturated fatty acids such as palmitate synergizes with temozolomide treatment. Pharmacological inhibition of SCD and/or FADS2 allows palmitate accumulation and thus greatly augments temozolomide efficacy. This effect was independent of common GBM prognostic factors and was effective against cancer cells from recurring glioblastoma. In summary, we provide evidence that intracellular accumulation of saturated fatty acids in conjunction with temozolomide based chemotherapy induces death in glioblastoma cells derived from patients.

胶质母细胞瘤是一种高致命性的星形细胞瘤，其平均生存期极短。尽管投入了大量的研究努力，但仍缺乏能够改善这些前景的替代方案。我们发现，化疗药物替莫唑胺对新诊断的胶质母细胞瘤的脂肪酸合成和去饱和化产生了影响。然而，这种反应在来自同一患者的复发性胶质母细胞瘤中却变得迟钝。此外，我们描述了通过破坏细胞脂肪酸稳态，以促进饱和脂肪酸（如棕榈酸）的积累，可以与替莫唑胺治疗产生协同作用。SCD和/或FADS2的药理抑制允许棕榈酸的积累，从而极大地增强了替莫唑胺的疗效。这一效应与常见的胶质母细胞瘤预后因素无关，且对复发性胶质母细胞瘤的癌细胞有效。总之，我们提供了证据，表明与基于替莫唑胺的化疗相结合的细胞内饱和脂肪酸的积累可诱导源自患者的胶质母细胞瘤细胞的死亡。