The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells
The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells
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DOI：
10.1080/15548627.2020.1761651
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发表时间：
2020-05-25
期刊：
影响因子：
13.3
通讯作者：
Lizcano, Jose M.
中科院分区：
文献类型：
--
作者：
Munoz-Guardiola, Pau;Casas, Josefina;Lizcano, Jose M.
ABTL0812是一种具有抗癌活性的一流小分子，目前正在进行晚期子宫内膜癌和鳞状非小细胞肺癌患者的2期临床试验（NCT03366480）。此前，我们发现 ABTL0812 诱导 TRIB3 假激酶表达，从而抑制 AKT-MTORC1 轴和巨自噬/自噬介导的癌细胞死亡。然而，ABTL0812引起的细胞毒性自噬的精确分子决定因素仍不清楚。通过广泛的生化和脂质组学分析，我们证明ABTL0812通过损害DEGS1（δ4-去饱和酶，鞘脂1）活性来增加细胞长链二氢神经酰胺，从而导致持续的内质网应激并通过ATF4-DDIT3-TRIB3激活未折叠蛋白反应（UPR），最终促进细胞毒性 癌细胞中的自噬。因此，增加细胞二氢神经酰胺的药理学操作或与外源二氢神经酰胺一起孵育会导致内质网应激、UPR和自噬介导的癌细胞死亡。重要的是，我们优化了一种方法来量化参加正在进行的临床试验的患者血液样本中的 mRNA，这些患者的 DDIT3 和 TRIB3 mRNA 显着增加。这是首次报道 UPR 标记物在人类血液中因任何药物治疗而发生变化，支持它们用作激活人类 ER 应激的化合物的药效生物标记物。最后，我们发现 MTORC1 抑制和二氢神经酰胺积累协同诱导自噬和细胞毒性，与 ABTL0812 的效果相似。鉴于 ABTL0812 正处于临床开发阶段，我们的研究结果支持这样的假设：控制二氢神经酰胺水平可能代表一种针对癌症的新治疗策略。
ABTL0812 is a first-in-class small molecule with anti-cancer activity, which is currently in clinical evaluation in a phase 2 trial in patients with advanced endometrial and squamous non-small cell lung carcinoma (NCT03366480). Previously, we showed that ABTL0812 induces TRIB3 pseudokinase expression, resulting in the inhibition of the AKT-MTORC1 axis and macroautophagy/autophagy-mediated cancer cell death. However, the precise molecular determinants involved in the cytotoxic autophagy caused by ABTL0812 remained unclear. Using a wide range of biochemical and lipidomic analyses, we demonstrated that ABTL0812 increases cellular long-chain dihydroceramides by impairing DEGS1 (delta 4-desaturase, sphingolipid 1) activity, which resulted in sustained ER stress and activated unfolded protein response (UPR) via ATF4-DDIT3-TRIB3 that ultimately promotes cytotoxic autophagy in cancer cells. Accordingly, pharmacological manipulation to increase cellular dihydroceramides or incubation with exogenous dihydroceramides resulted in ER stress, UPR and autophagy-mediated cancer cell death. Importantly, we have optimized a method to quantify mRNAs in blood samples from patients enrolled in the ongoing clinical trial, who showed significant increasedDDIT3andTRIB3mRNAs. This is the first time that UPR markers are reported to change in human blood in response to any drug treatment, supporting their use as pharmacodynamic biomarkers for compounds that activate ER stress in humans. Finally, we found that MTORC1 inhibition and dihydroceramide accumulation synergized to induce autophagy and cytotoxicity, phenocopying the effect of ABTL0812. Given the fact that ABTL0812 is under clinical development, our findings support the hypothesis that manipulation of dihydroceramide levels might represents a new therapeutic strategy to target cancer.